Characterization of patients with aggressive
adult T-cell leukemia–lymphoma in
Okinawa, Japan: a retrospective analysis ofa large cohort
Yukiko Nishi, Takuya Fukushima,
Shogo Nomura, Takeaki Tomoyose,
Sawako Nakachi, Kazuho Morichika, Iori
Tedokon, Keita Tamaki, et al.
International Journal of Hematology
ISSN 0925-5710
Int J Hematol
DOI 10.1007/s12185-016-2042-y

1 23

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Author's personal copy
Int J Hematol
DOI 10.1007/s12185-016-2042-y

ORIGINAL ARTICLE

Characterization of patients with aggressive adult T‑cellleukemia–lymphoma in Okinawa, Japan: a retrospective analysis
of a large cohort
Yukiko Nishi1 · Takuya Fukushima2 · Shogo Nomura3 · Takeaki Tomoyose1 ·Sawako Nakachi1 · Kazuho Morichika1 · Iori Tedokon1 · Keita Tamaki1 ·Natsuki Shimabukuro1 · Naoya Taira4 · Takashi Miyagi4 · Kaori Karimata4 ·Masayo Ohama4 · Atsushi Yamanoha4 · Kazumitsu Tamaki5 · Masaki Hayashi6 ·Hitoshi Arakaki7 · Jun‑Nosuke Uchihara7 · Kazuiku Ohshiro8 · Yoshitaka Asakura9 ·Megumi Kuba‑Miyara2 · Kennosuke Karube10 · Hiroaki Masuzaki1

Received: 5 April 2016 / Revised: 15 June 2016 / Accepted: 15 June 2016
© The Japanese Society of Hematology 2016

Abstract Okinawa Prefecture, located in the subtropics, isan area of endemic adult T-cell leukemia–lymphoma (ATL)in Japan. We retrospectively analyzed 659 patients withaggressive ATL in seven institutions in Okinawa between
2002 and 2011. The median patient age was 68 years. Morepatients were aged ≥90 years (2.6 %), in this study, thanin a nationwide survey (<1 %). The median survival time(MST) of the entire cohort was 6.5 months. Of the 217
patients who had a clinical status similar to that stated in
the eligibility criteria of JCOG9801 (a randomized phase
III study comparing VCAP-AMP-VECP with CHOP14), 147 who received the CHOP regimen had a poorer
MST than those in the CHOP-14 arm of JCOG9801 (8 vs11 months). The prevalence of strongyloidiasis in the ATL
patients was much higher (12.4 %) than in the historicalcohort who visited the University of the Ryukyus Hospital(3.4 %). Furthermore, strongyloidiasis may be associatedwith ATL-related deaths. These findings suggest that, compared with other areas in Japan, in Okinawa, the proportionof patients aged ≥90 years with clinical features of aggressive ATL is higher, outcomes are poorer, and the disease isassociated with a higher prevalence of strongyloidiasis.

* Takuya Fukushima
fukutaku@med.u‑ryukyu.ac.jp

5Department of Hematology, Okinawa Prefectural Chubu
Hospital, Uruma, Japan

6

Department of Hematology, Nakagami Hospital, Okinawa,
Japan

7

Department of Hematology, Naha City Hospital, Naha, Japan

8

Department of Hematology, Okinawa Prefectural Nambu
Medical Center and Children’s Medical Center, Haebaru,
Japan

9

Department of Hematology, Okinawa Red Cross Hospital,
Naha, Japan10

Department of Pathology and Cell Biology, Graduate Schoolof Medicine, University of the Ryukyus, Nishihara, Japan

1

Division of Endocrinology, Diabetes and Metabolism,
Hematology (Second Department of Internal Medicine),
Graduate School of Medicine, University of the Ryukyus,
Nishihara, Japan

2

Laboratory of Hematoimmunology, School of Health
Sciences, Faculty of Medicine, University of the Ryukyus,
207 Uehara, Nishihara, Okinawa 903‑0215, Japan

3

Biostatistics Division, Center for Researchand Administration and Support, National Cancer Center,
Tokyo, Japan

4

Keywords Adult T-cell leukemia–lymphoma · Okinawa ·Retrospective analysis · Subtropics · Strongyloidiasis

Introduction
Adult T-cell leukemia–lymphoma (ATL) is a distinct
peripheral T-cell neoplasm associated with human T-lymphotropic virus type-I (HTLV-1) [1–5]. Classificationof clinical subtypes into acute, lymphoma, chronic, andsmoldering was proposed based on prognostic factors,

Department of Hematology, Heartlife Hospital, Nakagusuku,
Japan

13

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Y. Nishi et al.

clinical features, and natural history of the disease [6].
Patients with aggressive ATL (i.e., acute, lymphoma, andunfavorable chronic types) have frequently been treated asa subtype of aggressive non-Hodgkin lymphoma (NHL),
whereas those with indolent ATL (i.e., favorable chronicand smoldering types) have been managed as a subtype ofchronic lymphoid leukemia [7, 8]. Multicenter clinical trials for patients with aggressive ATL run by the Japan Clinical Oncology Group (JCOG) have revealed that aggressive ATL has a very poor prognosis compared with othertypes of aggressive NHL [9–12]. The best chemotherapy
results for those patients were seen in the phase II and III
trials evaluating the chemotherapy regimen of VCAPAMP-VECP for aggressive ATL. This dose-intensified,multi-agent chemotherapy consisted of vincristine (VCR),
cyclophosphamide (CPA), doxorubicin (DXR), and prednisone (PSL) (=VCAP); DXR, ranimustine, and PSL(=AMP); and vindesine, etoposide, carboplatin, and PSL(=VECP). Based on the promising results of the phase II
trial JCOG9303 [13], the phase III trial JCOG9801 was
conducted to compare the VCAP-AMP-VECP and CHOP
(VCR, CPA, DXR, and PSL)-14 regimens [14]. The complete response (CR) and 3-year overall survival (OS) werehigher in the VCAP-AMP-VECP arm than in the CHOP-14
arm (40 vs 25 %, and 24 vs 13 %, respectively), suggesting that the former is a more effective regimen for patientswith newly diagnosed aggressive ATL. Recently, allogeneic
hematopoietic stem cell transplantation (allo-SCT) using
myeloablative and reduced intensity conditioning for somepatients with aggressive ATL has been reported to cure thedisease associated the graft-versus-ATL effect, despite its
high transplant-related mortality [15–17]. The 3-year OS
rate was about 40 % in allo-SCT from human leukocyte
antigen (HLA)-matched related and unrelated donor [15].
In Japan, nationwide surveys have been conducting
intermittently since the 1980s. The 4th Japan nationwide
survey of 657 patients with all subtypes of ATL from 1986
to 1987 at 191 institutions (including 2 institutions in
Okinawa) demonstrated that among all ATL patients registered, 5 % were from Kyushu, and no sex difference inthe average age of ATL patients was observed (i.e., averageage of 358 men and 295 women was 57.5 and 57.8 years,
respectively) [18]. The 9th Japan nationwide survey of all
ATL subtypes in 910 patients from 2006 to 2007 at 156
institutions (including 2 institutions in Okinawa) [19] demonstrated that median age was higher at 67 years and thatthe peak number of patients was in the 1970s age group,
which was a shift from the previous peak in the 1950s age
group in the 4th nationwide survey [18].
Okinawa Prefecture, located in the only subtropical area
in Japan (Fig. 1), is an area endemic for ATL [18]. However,no large-scale retrospective analysis of ATL in Okinawa has

13

Fig. 1  Location of Okinawa Prefecture (black) in East Asia

been conducted to date, and therefore, differences in theclinical features of ATL between Okinawa and other areasof Japan as well as distinguishing characteristics related
to the subtropics are yet to be elucidated. In this study, we
aimed to characterize the clinical features by retrospectively examining a large number of patients (n = 659) withaggressive ATL in 7 institutions in Okinawa Prefecture.

Patients and methods
Study design and data collection
This was a retrospective analysis of patients with aggressive ATL from 7 institutions (University of the Ryukyus
Hospital, Okinawa Prefecture Chubu Hospital, Heartlife
Hospital, Nakagami Hospital, Naha City Hospital, Nambu
Medical Center, and Okinawa Red Cross Hospital) in
Okinawa Prefecture from January 2002 to December 2011.
The ethics committee at each center reviewed and approved
the protocol. A standardized clinical data form was distributed to each participating center in the registry (2012–2013). The collected data were reviewed and checked byexpert hematologists (T.F., T.T., N.T., K.T., M.H., J.U.,
K.O., and Y.A.) and data manager (M.K.M). The latest dataassociated with prognosis were collected at the time of theinvestigation. The inclusion criteria were based on seropositivity for the anti-HTLV-1 antibody and histologically and/or cytologically proven peripheral T-cell malignancy.

Author's personal copy
Characterization of patients with aggressive adult T cell leukemia–lymphoma in…

The examination of Strongyloides stercoralis infection
was routinely checked by microscopic stool analysis on
admission in each hospital.
Definitions of clinical endpoint and responses
The endpoint of this study was OS, defined as the duration
between diagnosis and death from any cause or censored at
the last follow-up in living patients. The response criteria
used in this report followed those established by JCOG [13,14]. CR was defined as the disappearance of all clinicaland radiographic evidences of disease and the normalization of lactate dehydrogenase (LDH). Partial response (PR)was defined as ≥50 % reduction of measurable disease
with more than 75 % reduction in the absolute abnormal
lymphocyte count. LDH had to be decreased to <1.5 of thenormal upper limit. Progressive disease (PD) was definedas ≥25 % increase of the measurable disease or the appearance of new lesions during treatment. Stable disease (SD)was defined as an intermediate response between PR andPD.
Statistical analysis
Survival curves were estimated using the Kaplan–Meiermethod and compared using the log-rank test. The effect ofinfection with strongyloidiasis and the cause of death weresummarized by cross tabulation.
To compare the prognosis of patients with aggressive
ATL in Okinawa Prefecture with the JCOG9801 result [14],we extracted patients who had met almost the same eligibility criteria as those of JCOG9801: <70 years old, Eastern Cooperative Oncology Group (ECOG) performancestatus 0–3, platelet count ≥100,000/μL, creatinine levels≤2.0 mg/dL, and aspartate aminotransferase and alanine
aminotransferace <100 IU/L. Then, we evaluated prognosis
by chemotherapeutic regimen (VCAP-AMP-VECP, CHOP,
or others).
All statistical analyses were performed using SAS
Release 9.3 (SAS institute, Inc, Cary, NC) and STATA software Release 13 (Stata Corporation, College Station, TX).

Results
This study involved 659 patients with acute, lymphoma,
and unfavorable chronic and smoldering types with skinlesions treated with chemotherapy. The clinical characteristics of patients are summarized in Table 1. There
were missing data on the cause of death in 2 cases. The
median age was 68 years, and the age of onset group withthe largest patient number for both men and women was
the 70–79 group. Surprisingly, the highest age of onset

was 102 years and the ≥90 age group constituted 2.6 %(n = 17) of all 659 patients (Table 2). The most common
treatment employed was a CHOP-like regimen (n = 366 intotal; CHOP, n = 360; CHOP + etoposide, n = 6). Only 44
patients received VCAP-AMP-VECP. Of 548 patients who
received chemotherapy, 302 patients (49 %: 134 CR and
168 PR) responded to treatment, and 310 patients (50 %;141 SD and 169 PD) were resistant to initial chemotherapy.
Forty-one patients did not receive any treatment.
Survival analysis and its comparison with JCOG9801
The median follow-up period was 12.5 (range 0–125)
months. At the time of the last follow-up, 110 patients,
including 12 patients who received allo-SCT, were alive
and 548 patients had died [453 had disease progression, 7
had an adverse reaction to chemotherapy, 18 had transplantrelated toxicity, and 68 died from other causes (1 not evaluable)]. The MST and 2-year OS of the entire cohort were
6.5 months and 19 %, respectively (Fig. 2a). The MST and
2-year OS rate by treatment regimen were 7 months and
19 % with the CHOP regimen, 10 months and 29 % with
the VCAP-AMP-VECP regimen, and 6 months and 16 %with other regimens, respectively (Fig. 2b).
Patients who roughly met the same eligibility criteria
as those of JCOG9801 were extracted (n = 217, including
8 patients without therapy). The characteristics of the 217
patients in our study and the 118 patients in JCOG9801
are listed in Table 3. The MST was 8 months in the 147
patients who received the CHOP regimen and 9.6 months
in the 22 patients who received the VCAP-AMP-VECP
regimen (Fig. 3), compared with 11 and 13 months in
the CHOP-14 arm and VCAP-AMP-VECP arm of theJCOG9801, respectively.
Allo‑SCT
Of the 659 patients studied, 46 patients received allo-SCT
with myeloablative (n = 20) and reduced intensity (n = 26)
conditioning. The clinical characteristics of the patients are
summarized in Table 4. At the time of the last follow-up, 12
patients were alive and 34 had died (14 PD, 18 transplantrelated toxicity, and 2 deaths from other causes). MST and
3-year OS after diagnosis were 1.5 years and 29.3 % inpatients who received allo-SCT, and 0.5 years and 11.5 %in those who did not (Fig. 4).
Strongyloidiasis
Okinawa Prefecture, a subtropical region of Japan, is
known as an endemic area for S. stercoralis infection. The
prevalence rate of the entire cohort was 12.4 %, which
is higher than the rate of 3.4 % in the 3,992 patients,

13

Author's personal copy
Y. Nishi et al.

NE

341/31868 (26–102)
366 (56 %)
233 (35 %)
56 (8 %)
4 (1 %)
51 (8 %)
284 (43 %)
151 (23 %)
119 (18 %)
50 (8 %)
4 (<1 %)
168 (25 %)
346 (53 %)
145 (22 %)
366 (56 %)
44 (7 %)
131 (20 %)
19 (3 %)
55 (8 %)
41 (6 %)
3 (<1 %)
134 (20 %)
168 (25 %)
141 (21 %)
169 (26 %)
47 (7 %)
453 (83 %)
7 (1 %)
18 (3 %)
68 (12 %)
2 (<1 %)

ATL adult T-cell leukemia–lymphoma, PS performance status, NE
not evaluated, Ca calcium, CHOP cyclophosphamide, doxorubicin,
vincristine, prednisone, VCAP-AMP-VECP cyclophosphamide, doxorubicin, vincristine, ranimustine, vindesine, carboplatin, etoposide,
prednisone, ETP etoposide, PSL prednisone, THP-COP pirarubicin,
cyclophosphamide, vincristine, prednisone, CR complete response,
PR partial response, SD stable disease, PD progressive disease, AE
adverse eventa

Because of missing data on Ca (n = 39) and albumin (n = 106)

including a few patients in the present study, who visited
the University of the Ryukyus Hospital from January 2004
to November 2006 [20]. In each age group, the prevalence13

Age group

Male

FemaleTotal≥20, <30≥30, <40≥40, <50≥50, <60≥60, <70≥70, <80≥80, <90

1 (0.2 %)1 (0.2 %)
25 (0.2 %)
75 (22 %)
99 (29 %)
103 (30 %)
30 (9 %)

1 (0.3 %)
5 (2 %)
10 (3 %)
72 (20 %)78 (23 %)
94 (27 %)48 (15 %)

2 (0.3 %)6 (0.9 %)35 (5.3 %)
147 (22.3 %)
177 (26.9 %)
197 (30.0 %)78 (11.8 %)

7 (2 %)

10 (3 %)

17 (2.6 %)≥90

ATL adult T-cell leukemia–lymphoma

A 1.0
Proportion alive (%)

Sex (male/female)Median age (range)
Subtype of ATL
Acute
Lymphoma
Unfavorable chronic
Smoldering (skin type)
PS
0
1
2
3
4
NE
Corrected Ca (mg/dL)≥11.0 mg
<11.0
NEa
Chemotherapy regimen
CHOP or CHOP-like
VCAP-AMP-VECP
ETP with or without PSL
THP-COP
Other
No therapy
NE
Response to the initial chemotherapy
CR
PR
SD
PD
NE
Cause of death (total 548)
Disease progression
Chemotherapy-related AEs
Transplant-related toxicity
Other

Table 2  Distribution of patients with aggressive ATL according toage group

0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0

0

1

2

3

MST: 6.5 months(n=659)

4

8

5

6

7

9

10

11

12

Years after diagnosis

B
Overall survival (probability)

Table 1  Clinical characteristics of all 659 patients

1.0
0.9

MST

MST
of JCOG9801

0.8
0.7

CHOP regimen (n=360)

7 months

11 months

0.6

VCAP-AMP-VECP regimen (n=44) 10 months

13 months

0.5

Others (n=209)

6 months

0.4
0.3
0.2

Log-rank P=0.094

0.1
0.0

0

1

No. at risk
CHOP 360 97
VCAPAMP- 44 17
VECP
Others 209 63

2

3

4

5

6

7

8

9

10

11

55

33

22

17

12

8

4

4

1

0

11

7

4

1

0

25

12

10

6

4

3

3

1

0

Years after diagnosis

12

Fig. 2  Overall survival (OS) of the entire cohort and according to treatment regimens. a OS of all 659 patients with aggressive
ATL. Median survival time (MST) was 6.5 months. b OS according to different treatment regimens. MST was 7 months with CHOP,
10 months with VCAP-AMP-VECP, and 6 months with others

rate was higher in the present study than in the previous
study (Fig. 5). Among 81 patients with strongyloidiasis
and 574 patients without strongyloidiasis, 12 (15 %) and97 (17 %) survived, and 63 (78 %) and 390 (68 %) died of
ATL, respectively (Table 5).

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Characterization of patients with aggressive adult T cell leukemia–lymphoma in…
Table 3  Characteristics of
217 patients who had clinicalcharacteristics similar to theeligibility criteria of JCOG9801
and the 118 patients of
JCOG9801

Our study (n = 217)
Age
Median
Range
Sex
Male
FemaleSubtypeAcute
Lymphoma
Unfavorable chronic
Smoldering
PS
0
1
2
3
4
Regimen
CHOP
VCAP-AMP-VECP
Other
No therapy

JCOG9801
VCAP-AMP-VECP (n = 57)

Biweekly CHOP (n = 61)

59
28–69

56
36–69

58
33–69

102 (47 %)
115 (53 %)

27 (47 %)
30 (53 %)

34 (56 %)
27 (44 %)

117 (54 %)
77 (35 %)
22 (10 %)1 (0.5 %)

40 (70 %)
12 (21 %)
5 (9 %)
0 (0 %)

41 (67 %)
14 (23 %)
6 (10 %)
0 (0 %)

20 (9 %)
131 (60 %)
45 (21 %)
21 (10 %)0 (0 %)

19 (33 %)
27 (47 %)
8 (14 %)
2 (4 %)
1 (2 %)

30 (49 %)
19 (31 %)
10 (16 %)
2 (3 %)
0 (0 %)

147
22
40
8

Overall survival (probability)

ATL adult T-cell leukemia–lymphoma, CHOP cyclophosphamide, doxorubicin, vincristine, prednisone,
VCAP-AMP-VECP cyclophosphamide, doxorubicin, vincristine, ranimustine, vindesine, carboplatin,
etoposide, prednisone, PS performance status

Discussion

1.0
0.9
0.8

MST

MST
of JCOG9801

8 months

11 months
13 months

0.7

CHOP regimen (n=147)

0.6

VCAP-AMP-VECP regimen (n=22)

10 months

0.5

Others (n=40)

12 months

0.4
0.3
0.2
0.1
0.0

Log-rank P=0.729

0No. at risk
CHOP 147
VCAPAMP- 22
VECP
Others 40

1

2

3

4

5

6

7

8

9

10

11

46

31

17

12

10

7

5

2

2

1

0

7

6

5

3

1

0

19

6

2

1

1

1

Years after diagnosis

120Fig. 3  OS of patients who roughly met the same eligibility criteria
as patients in the JCOG9801 study. MST was 8 months with CHOP,
10 months with VCAP-AMP-VECP, and 12 months with others

This was the first retrospective analysis of a large cohort ofpatients with aggressive ATL in Okinawa Prefecture, and it
revealed the clinical features of the disease, namely, morepatients aged ≥90 years, possibly poorer outcome compared with that of other areas in Japan, and association witha high frequency of S. stercoralis infection. In particular,
we clarified for the first time that strongyloidiasis could be
an important issue for patients with aggressive ATL in thesubtropics.
In this analysis, the median age of all 659 patients withaggressive ATL was 68 years, which was almost the sameas the age of 67 years of the 910 patients in the nationwide survey of all ATL subtypes from 2006 to 2007 in
Japan (including some patients in two institutions in thepresent study) [19]. However, the proportion of patients
aged ≥90 years was 2.6 %, compared with <1 % in the13Author's personal copy
Y. Nishi et al.
Table 4  Clinical characteristics of 46 patients who received all-SCT
Sex (male/female)Median age (range)
Subtype of ATL
Acute
Lymphoma
Unfavorable chronic
Disease status at transplantation
CR
PR
SD
PD
NE
PS at transplantation
1
2
3
4
NE
Conditioning regimen
Myeloablative
Reduced intensity
Donor
RelatedUnrelated
Cord blood
Cause of death (total 34)
Disease progression
Transplant-related toxicity

4
18

Other

2

19/27
51 (26–68)

Overall survival (probability)

This study

18

29
16
1

16

Prevalence rate (%)

14

16
19
5
5
1

12
10
8
6
4

2
32
5
5
2

2
0

30
13
3

0.8

40-59

60-79

>80

total

Table 5  Association between strongyloidiasis and cause of death(n = 655)

No Transplant (n=613)

0.9

20-39

Fig. 5  Comparison of the prevalence rate of strongyloidiasis in eachage group between the present study and the previous study at the
University of the Ryukyus Hospital. The prevalence rate in the present study was higher than that in the previous study, which was mostnotable in the 1920s and 1930s age groups

20
26

1.0

0-19

Age group

ATL adult T-cell leukemia–lymphoma, CR complete response, PRpartial response, SD stable disease, PD progressive disease, NE notevaluated, PS performance status

Strongyloidiasis

Yes (n = 81)

No (n = 574)

Survival
ATL-related death
Other cause of death
Treatment-related death

12 (15 %)
63 (78 %)
5 (6 %)
1 (1 %)

97 (18 %)
390 (68 %)
63 (11 %)
6 (1 %)

Transplant-related death0

18 (3 %)

ATL adult T-cell leukemia–lymphoma

Transplant (n=46)

0.7
0.6
0.5
0.4
0.3

3-year OS: 29.3%

0.2
0.1
0.0

Previous report of
University of the
Ryukyus3-year OS: 11.5%

0

1

2

3

4

5

6

7

Years after diagnosis

8

9

10

11

12

Fig. 4  OS of patients who received (transplant) or did not receive (notransplant) allogeneic hematopoietic stem cell transplantation. Threeyear OS was 29.3 % with transplant and 115 % with no transplant

13

nationwide survey. Moreover, there were 2 patients aged≥100 years, and a 102-year-old patient was the oldest in
this analysis. There were more patients in the ≥90 age
group in Okinawa Prefecture than in the other areas inJapan.
The MST of the entire cohort in this study was
6.5 months, which is a poorer outcome compared withapproximately 8 months in the previous reports [6–11].
Furthermore, in 217 patients who had clinical conditions
similar to those in the eligibility criteria of JCOG9801, theMST was poorer in both patients who received the CHOP
regimen and those who received the VCAP-AMP-VECP

Author's personal copy
Characterization of patients with aggressive adult T cell leukemia–lymphoma in…

regimen than in the CHOP-14 arm and VCAP-AMP-VECP
arm of JCOG9801 [14] (Fig. 3). These findings suggestthat patients with aggressive ATL in Okinawa might have apoorer response to chemotherapy than those in other areasin Japan. The MST of other regimens in the comparison
set was superior to that of the CHOP and VCAP-AMPVECP regimens. However, the regimens were heterogeneous, and also, the long-term survival rate was extremely
poor (Fig. 3). When considering these points, it is not soimportant to evaluate the reason for the better outcome inthe other regimen group.
In this study, 50 % of patients were resistant to the initial chemotherapy, and 83 % of patients died from disease progression. On the other hand, the overall response
rate (CR and PR) in JCOG9801 was 72 and 66 % in the
VCAP-AMP-VECP arm and CHOP-14 arm, respectively.
This observation further supports the idea that early disease-related death could be associated with the poorer
outcome in Okinawa. The results of JCOG9801 suggested
that VCAP-AMP-VECP is a more effective regimen than
CHOP-14 at the expense of greater toxicity in patients
aged <70 years with newly diagnosed aggressive ATL [14].
In addition, the Nagasaki Group reported that the VCAPAMP-VECP regimen might be effective for elderly patientswith aggressive ATL [21]. Of all 659 registered patientsin this study, 366 (56 %) received the CHOP regimen or a
CHOP-like regimen, but only 44 (7 %) received the VCAPAMP-VECP regimen. Recently, the randomized phase II
study of VCAP-AMP-VECP with or without mogamulizumab, a human anti-CC chemokine receptor 4 antibody,demonstrated that %CR and overall response rate in the
mogamulizumab-plus-VCAP-AMP-VECP arm (52 and
86 %, respectively) were superior to those in the VCAPAMP-VECP arm (33 and 75 %, respectively) [22]. Further
investigation of mogamulizumab-plus-VCAP-AMP-VECP
is needed to improve the outcome for newly diagnosed
aggressive ATL in Okinawa.
As mentioned earlier, the nationwide retrospective studyof allo-SCT for ATL in Japan demonstrated that 3-year OS
was 33 % for the whole cohort and approximately 40 %in HLA-matched related and unrelated graft recipients[15]. Of the 659 patients in the present study, 46 received
allo-SCT. The MST and 3-year OS of these patients were
1.5 years and 29.3 %, respectively (Fig. 4). The evaluationof the efficacy of allo-SCT in Okinawa was hindered by theheterogeneity of the disease status at the time of transplantation, and variation in the duration from diagnosis to transplantation and transplant procedures.
Okinawa Prefecture is an endemic area for S. stercoralis infection, which frequently occurs in the subtropics. In
this study, we found a higher prevalence rate of strongyloidiasis (12.4 %) in patients with aggressive ATL compared with the previous data on 3,292 patients who visited

the University of the Ryukyus Hospital [20] (Fig. 4). Previous reports demonstrated that concurrent infection of S.
stercoralis in HTLV-1 carriers was highly associated withparasite dissemination and development of severe strongyloidiasis [23–27]. In our series, it was demonstrated
that strongyloidiasis might be associated with ATL-related
deaths (78 % with strongyloidiasis vs 68 % without strongyloidiasis). However, it is not clear whether strongyloidiasis influences the survival of patients with aggressive ATL.
Further evaluation involving a multivariate analysis, including S. stercoralis infection, as one of covariates is needed.
This study had an inherent limitation that some essential data may be insufficient or inaccurate, because we collected clinical data retrospectively. For example, disease
subtype could not be fully evaluated, because of missing
data, and information on dosing of CHOP or VCAP-AMPVECP was limited. In addition, due to the nature of theobservational study, comparison of OS across treatment
regimens might have been biased, because treatment wasdetermined by the physicians of each institution, not randomly. We addressed this limitation by extracting patients
who roughly met the same eligibility criteria as those of
JCOG9801 and compared their prognosis with those in theprevious study.
In conclusion, patients with aggressive ATL in Okinawa
might have different clinical features compared withthose in other areas in Japan, namely more patients aged
≥90 years, poorer outcome, and a higher prevalence ofstrongyloidiasis. To investigate the cause of clinical features and to improve the treatment outcome, biologicalanalyses using cells from patients with ATL and HTLV-1
carriers are needed in Okinawa.
Acknowledgments This work was supported by a grant from
Okinawa Prefecture, Japan (grant to T.F. and T.T.).
Compliance with ethical standards
Conflict of interest The authors report no potential conflict of interest.

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