Allogeneic hematopoietic stem cell transplantation provides sustained long-term
survival for patients with adult T-cell leukemia/lymphoma
T Fukushima1, Y Miyazaki1, S Honda2, F Kawano3, Y Moriuchi4, M Masuda5, R Tanosaki6, A Utsunomiya7, N Uike8, S Yoshida9,
J Okamura8 and M Tomonaga1
1Department of Hematology, Molecular Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University Graduate School of
Biomedical Sciences, Nagasaki, Japan; 2Department of Radiation Epidemiology, Radiation Effect Research Unit, Atomic Bomb
Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; 3Institute for Clinical Research,
Kumamoto National Hospital, Kumamoto, Japan; 4Department of Internal Medicine, Sasebo City General Hospital, Sasebo, Japan;
5Second Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus, Naha, Japan; 6Stem Cell Transplant
Unit, National Cancer Center Hospital, Tokyo, Japan; 7Department of Hematology, Imamura Bun-in Hospital, Kagoshima, Japan;
8Department of Hematology and the Section of Pediatrics, National Kyushu Cancer Center, Fukuoka, Japan; and 9Department of
Hematology, National Nagasaki Medical Center, Ohmura, Japan
Adult T-cell leukemia/lymphoma (ATLL) is a distinct peripheral
T-cell neoplasm that is highly resistant to chemotherapy.
Several groups, including ours, have reported encouraging
results of allogeneic hematopoietic stem cell transplantation
(allo-HSCT) for patients with ATLL. To confirm our previous
report and to establish the basis for a phase II clinical study, we
analyzed 40 allo-HSCT for acute and lymphoma types of ATLL
in seven institutions in Japan between 1997 and 2002. All
evaluable cases entered complete remission (CR) after allo-
HSCT and the median survival time was 9.6 months for all
patients. The estimated 3-year overall and relapse-free survival,
and disease relapse were 45.3, 33.8 and 39.3%, respectively.
Among 10 cases with ATLL relapse, five cases achieved CR
again: three by the reduction or cessation of immunosuppres-
sive agents, which suggested a graft-versus-ATLL (GvATLL)
effect. However, univariate or multivariate analysis did not
show any benefit of graft-versus-host disease (GVHD) on the
prevention of relapse. These results suggested that allo-HSCT
was effective for some patients with aggressive ATLL, and that
the GvATLL effect could be achieved even without GVHD. A
new phase II trial to test the efficacy of allo-HSCT for ATLL is
warranted.
Leukemia (2005) 19, 829–834. doi:10.1038/sj.leu.2403682
Published online 3 March 2005
Keywords: ATLL; allogeneic HSCT; GvATLL
Introduction
Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell
neoplasm associated with the infection of a specific retrovirus,
human T-cell lymphotropic virus type-I (HTLV-I).1–4 ATLL is
quite different from other types of non-Hodgkin’s lymphoma
(NHL): restricted endemic areas including the west coast of
Japan, with distinct clinical features such as high frequency of
hypercalcemia, a strong predisposition to infection and poor
response to chemotherapy.4,5 Multicenter clinical trials for ATLL
conducted by the Japan Clinical Oncology Group (JCOG) have
shown that standard-dose chemotherapy for NHL was unable to
cure any patients with acute or lymphoma types of ATLL, which
is more aggressive than the chronic or smoldering type.5–7 The
best chemotherapy result for those patients was obtained from
the phase II trial of a new multidrug regimen containing nine
agents with the support of granulocyte colony-stimulating factor
(JCOG9303, LSG15 protocol).8 The overall survival (OS) rate of
the 93 patients in this trial was estimated at 31% at 2 years. In
these circumstances, high-dose chemotherapy/radiotherapy
with hematopoietic stem cell transplantation (HSCT) was
applied to those patients, particularly in Japan. The results of
allogeneic, not autologous, HSCT reported by several groups,
including ours, suggested that it could provide durable clinical
responses for some patients with ATLL.9–14 However, the
number of patients in each report was so small that the efficacy
of allogeneic HSCT (allo-HSCT) for ATLL is still controversial. In
this report, we aimed to extend our previous study to establish
the basis for a phase II clinical trial of allo-HSCT for aggressive
ATLL by retrospectively collecting a larger number (40) of
transplants from seven institutions in Japan. Our results
suggested that allo-HSCT is effective for some patients with
ATLL, and that there may be a graft-versus-ATLL (GvATLL) effect
that cannot be obtained by chemotherapy alone or high-dose
therapy with autograft.
Patients and methods
Study design, data collection and transplantation
procedure
This is a retrospective analysis of myeloablative allo-HSCT for
patients with ATLL performed at seven institutions in Japan from
June 1997 to April 2002. Data on donors and recipients were
collected using questionnaires distributed to each participating
center in this study. Patients included in this study received
intensive conditioning regimens prior to stem cell transplanta-
tion. The early results of the four out of 40 cases were reported
previously.14
Since transplantation was performed following the protocol of
each institution, the conditioning regimen or prophylaxis for
GVHD varied among institutions (Table 1); however, all but one
preconditioning regimens had myeloablative intensity (contain-
ing more than 12 Gy of total body irradiation (TBI, 22 cases),
16 mg/kg of busulfan (17 cases) and 140 mg/m2 of melphalan
(one case)).
Definitions of clinical end points and responses
The day of engraftment was defined as the first of 3 consecutive
days on which the neutrophil count exceeded 0.5
109/l.
Received 27 July 2004; accepted 7 January 2005; Published online 3
March 2005
Correspondence: Dr Y Miyazaki, Department of Hematology and
Molecular Medicine Unit, Atomic Bomb Disease Institute, Nagasaki
University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto,
Nagasaki 852-8523, Japan; Fax: þ 81 95 849 7113;
E-mail: y-miyaza@net.nagasaki-u.ac.jp
Leukemia (2005) 19, 829–834
& 2005 Nature Publishing Group All rights reserved 0887-6924/05 $30.00
www.nature.com/leu

Patients who died before day 28 were considered unevaluable
for engraftment. Relapse-free survival (RFS) was defined as the
time interval from transplantation to the first event (either
relapse or death in complete remission (CR)). Acute graft-versus-
host disease (aGVHD) was diagnosed and graded at each
transplantation center according to the standard criteria with
grades 0, I, II, III and IV.15 Chronic GVHD (cGVHD) was
defined according to standard criteria of absent, limited or
extensive.16 One patient, who received transplantation at the
stage of progressive disease (PD), died of infection on day 8 after
transplantation, and this case was excluded from the analysis of
engraftment, response to transplantation and GVHD. The
response criteria used in this report followed those established
by JCOG.8 CR was defined as the disappearance of all clinical
and radiographic evidence of disease and the normalization of
lactate dehydrogenase (LDH). As HTLV-I carriers frequently
have a small percentage of abnormal lymphocytes, CR was
judged with less than 5% of such cells if the absolute
lymphocyte count was less than 4
109/l. Partial response
(PR) was defined as a X50% reduction of the measurable
disease with more than 75% reduction in the absolute abnormal
lymphocyte count. LDH had to be decreased to o1.5 of the
normal upper limit. PD was defined by X25% increase of the
measurable disease or the appearance of new lesions while
under treatment. No change (NC) was defined by an inter-
mediate response between PR and PD.
Statistical analysis
The Kaplan–Meier method was used to estimate OS and RFS.
The 95% confidence intervals of 3-year OS and RFS were
calculated. For analyzing the relapse after transplantation, the
cumulative distribution function of relapse was calculated. The
differences in the OS and RFS rates between the groups of
transplantation-related factors were compared by the log-rank
test. Among those who reached CR after transplantation, the
differences in the proportion of ATLL relapse between the
groups of transplantation-related factors were compared by the
w2 test. Furthermore, simultaneous effects of prognostic factors
on survival (OS and RFS) and relapse were analyzed using
multivariate regression analysis based on the Cox’s proportional
hazards model and the linear logistic model, respectively. The
most appropriate models were selected based on Akaike’s
information criteria (AIC). All analyses were performed using
SAS (Statistical Analysis System Inc., Cary, NC, USA) software.17
Results
Patient characteristics and transplant conditions
Data on 40 transplantations were collected. The clinical
characteristics of patients are summarized in Table 1. All
patients received standard-dose chemotherapy before the
procedure of transplantation, and 28 patients (70%) showed a
clinical response to the previous chemotherapy. Nine related
donors showed a positive result for the anti-HTLV-I antibody.
The peripheral blood mononuclear cells of these donors were
subjected to Southern blot analysis to examine the monoclonal
integration of HTLV-I provirus into the genome, and all nine
donors were confirmed as carriers of HTLV-I.
Engraftment and response to transplantation
The median number of cells transplanted was 3.10. (1.20–
9.20)
108/kg of nucleated cells for bone marrow transplanta-
tion (21 cases) and 3.94 (1.20–8.30)
106/kg of CD34-positive
cells for peripheral blood stem cell transplantation (19 cases).
All evaluable patients (39 recipients) achieved engraftment and
the median time of neutrophil recovery to a level more than
0.5
109/l was 15 days (range 11–36). No case suffered from
late graft rejection. All patients who received transplantation
during PR disease status (13 cases) achieved CR after transplan-
tation. Of 11 patients with resistant disease (three NC and eight
PD) at the time of transplantation, 10 patients (except one PD
case) achieved CR.
GVHD and transplantation-related early toxicity
aGVHD developed in 26 of 39 patients (66.7%), and 15 out of
31 patients developed cGVHD (Table 2). There were 21 deaths
after transplantation, and 16 were related to adverse events
of transplantation (Table 2). Within 6 months after transplanta-
tion, 15 patients died: 13 were lost to adverse events of
transplantation.
Table 1 Patient characteristics and transplant condition
Sex (male/female) 22/18
Median age at transplantation (range) 44 (28–53)
Subtypes of ATLL
Acute 30
Lymphoma 10
Disease status at transplantation
CR1 14
CR2 1
PR 13
NC 3
PD 9
Performance status at transplantation
0 3
1 33
2 3
3 1
Donor
HLA-matched related 27
HLA-mismatched related 5
HLA-matched unrelated 8
Anti-HTLV-I antibody of donor
Positive 9
Negatine 27
NE 4
Source of stem cells
Bone marrow 21
Peripheral blood stem cell 19
Conditioning regimen
TBI-containing 18
Non-TBI-containing 22
GVHD prophylaxis
CsA+MTX 28
TCR+MTX 11
TCR 1
NE, not evaluable; CsA, ciclosporin; TCR, tacrolimus; MTX, methotor-
exate.
Sustained long-term survival of patients with ATLL after allo-HSCT
T Fukushima et al
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Leukemia