CASE REPORT

Successful treatment by donor lymphocyte infusion of adult T-cellleukemia/lymphoma relapse following allogeneic hematopoieticstem cell transplantation

Tomohiko Kamimura • Toshihiro Miyamoto • Noriaki Kawano •

Akihiko Numata • Yoshikiyo Ito • Yong Chong • Koji Nagafuji •

Takanori Teshima • Shin Hayashi • Koichi Akashi

Received: 20 September 2011 / Revised: 9 March 2012 / Accepted: 9 March 2012 / Published online: 6 April 2012

� The Japanese Society of Hematology 2012

Abstract Adult T-cell leukemia/lymphoma (ATLL) is a

highly aggressive hematologic neoplasm that has an

extremely poor prognosis; however, this has improved

following recent progress in allogeneic hematopoietic stem

cell transplantation (allo-HSCT). Several clinical studies

have shown that discontinuation of immunosuppressant

therapy induces durable remission in a significant number

of post-transplant relapsed patients, suggesting that ATLL

may be susceptible to a graft-versus-leukemia effect. Here,

we report two cases with ATLL who received donor

lymphocyte infusions (DLIs) for relapse after allo-HSCT;

one patient achieved complete remission (CR) after a sin-

gle DLI, and the other suffered repeated relapses and was

treated with chemotherapy and radiotherapy combined

with a total of five rounds of DLIs. Both patients presented

with exacerbation of the graft-versus-host disease after the

DLIs, and remained in CR for 9 and 8 years, respectively.

These data support the use of DLIs as an effective therapy

to induce durable CR in the treatment of relapsed ATLL. In

this study, we review previous reports and discuss the role

of DLIs in the treatment of post-transplant relapsed ATLL.

Keywords Adult T-cell leukemia/lymphoma �Donor lymphocyte infusion � Allo-HSCT �Graft-versus leukemia

Introduction

Adult T-cell leukemia/lymphoma (ATLL) is a highly

aggressive hematologic neoplasm of mature T lymphocytes

associated with infection of human T-cell lymphotropic

virus type 1 (HTLV-1) [1–3]. Patients with aggressive

ATLL have an extremely poor prognosis, because they are

resistant to conventional or high-dose chemotherapy; three-

year overall survival (OS) was reported to be about

10–20 % [4–6]. In contrast to the poor response to che-

motherapy, several Japanese groups have reported 3-year

OS of 30–40 % following allogeneic hematopoietic stem

cell transplantation (allo-HSCT) [7–11]. These studies

suggested that allo-HSCT induces an immunological

reaction, the so-called graft-versus-ATLL effect. Relapse

after allo-HSCT is still the major cause of treatment fail-

ure; however, many groups have reported that reduction or

discontinuation of immunosuppressant therapy effectively

induces a remission in relapsed ATLL following allo-

HSCT, consistent with the putative graft-versus-ATLL

effect [8, 9, 12, 13]. Thus, ATLL might be susceptible to a

graft-versus-leukemia (GvL) effect, similar to other

hematologic malignancies [14, 15]. However, there are few

reports describing the effectiveness of donor lymphocyte

infusions (DLIs) for post-transplant relapse of ATLL,

although DLI can augment further allogeneic immune-

mediated anti-tumor effect following allo-HSCT [16–19].

Here we report 2 cases of aggressive ATLL that are in

long-term remission following DLI and discuss the role of

DLI for post-transplant relapse of ATLL.

T. Kamimura � N. Kawano � Y. Ito � Y. Chong � S. Hayashi

Department of Hematology, Harasanshin Hospital, Fukuoka,

Japan

T. Miyamoto (&) � A. Numata � K. Nagafuji � T. Teshima �K. Akashi

Medicine and Biosystemic Science, Kyushu University Graduate

School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku,

Fukuoka 812-8582, Japan

e-mail: toshmiya@intmed1.med.kyushu-u.ac.jp

N. Kawano

Department of Internal Medicine,

Miyazaki Prefectural Hospital, Miyazaki, Japan

123

Int J Hematol (2012) 95:725–730

DOI 10.1007/s12185-012-1056-3

Table 1 Summary of allo-

PBSCT and donor lymphocyte

infusions

GVHD graft-versus-host

disease, DLI donor lymphocyte

infusion, CNS central nervous

system, PLT platelet, PR partial

response, CR complete

remission

Case 1 Case 2

Summary of allo-PBSCT

Age/sex 52/F 38/F

Subtype of ATL Lymphoma Lymphoma

Disease status at transplant PR CR

Donor HLA-identical

related donor

HLA-identical

related donor

Months from diagnosis to allo-PBSCT 2.7 4.5

Conditioning regimen TBI/CY TBI/CY

Infused CD34? cells (9106 cells/kg) 3.7 7.4

Engraftment

Neutrophil [0.5 9 109/L 15 15

PLT [20 9 109/L 15 23

Months from allo-PBSCT to first relapse 3.0 5.2

Acute GVHD before first relapse Grade II Grade II

Chronic GVHD before first relapse Limited None

First relapse

Relapse site Skin and peripheral blood Skin

Treatments except DLI None Chemotherapy

First DLI

Infused CD3? cells (9107 cells/kg) 1.0 1.0

GVHD after first DLI Grade III Grade II

Chronic GVHD after first DLI Extensive None

Second relapse

Relapse site CNS

Treatments except DLI Intrathecal chemotherapy,

and irradiation of the entire

brain and spine (20 Gy)

Second DLI

Infused CD3? cells (9107 cells/kg) 4.3

GVHD after second DLI None

Chronic GVHD after second DLI None

Third DLI

Infused CD3? cells (9107 cells/kg) 4.3

GVHD after third DLI None

Chronic GVHD after third DLI None

Third relapse

Relapse site Brachial plexus

Treatments except DLI Irradiation (30 Gy)

Fourth DLI

Infused CD3? cells (9107 cells/kg) 7.0

GVHD after fourth DLI None

Chronic GVHD after fourth DLI None

Fifth DLI

Infused CD3? cells (9107 cells/kg) 5.0

GVHD after fifth DLI None

Chronic GVHD after fifth DLI None

726 T. Kamimura et al.

123

Case presentation

Case 1

In August 2001, a 52-year-old Japanese woman presented

with systemic enlarged lymph nodes and subcutaneous

nodules on the entire body, and was diagnosed with lym-

phoma-type ATLL according to the criteria of the Japanese

Lymphoma Study Group [2]. The patient received combi-

nation CHOP chemotherapy including cyclophosphamide

(CY), vincristine, doxorubicin, and prednisone [20]. Two

courses of the CHOP regimen markedly reduced the size of

the subcutaneous tumors; however, ATLL cells subse-

quently appeared and increased rapidly in the peripheral

blood. In October 2001, she received a myeloablative

conditioning regimen consisting of 12 Gy total body irra-

diation (TBI) and 120 mg/kg CY, followed by allogeneic

peripheral blood stem cell transplantation (allo-PBSCT)

from an HLA-matched sibling (Table 1). Prophylaxis for

graft-versus-host disease (GVHD) consisted of cyclospor-

ine (CSP) and short-term methotrexate (MTX). Rapid

engraftment was achieved on day 15 after allo-PBSCT, and

the patient achieved complete remission (CR). Chimerism

analysis demonstrated that all bone marrow cells were

donor derived. On day 22, she developed skin eruptions

that were diagnosed as cutaneous, acute GVHD (grade II,

stage 3) by skin biopsy. Increased administration of CSP

resulted in a gradual clinical improvement in the acute

GVHD, and immunosuppressants were tapered. Since the

patient was considered to be at a high risk of relapse, CSP

was discontinued on day 47 to stimulate a graft-versus-

ATLL effect. The development of mild skin lichenoid

lesions indicated chronic GVHD; however, ATLL cells re-

appeared in the peripheral blood 95 days after allo-PBSCT.

Subcutaneous nodules that developed on her left thigh were

diagnosed as relapsed ATLL by skin biopsy.

On day 115 after allo-PBSCT, DLI from the same donor

was performed at a dose of 1.0 9 107 CD3? cells/kg. Since

the patient was still suffering from chronic GVHD at the

time, she was carefully followed without additional DLIs.

On day 90 after DLI, the patient presented with exacer-

bation of her GVHD affecting the skin, oral mucosa, and

liver, which coincided with the spontaneous disappearance

of the subcutaneous tumors and ATLL cells. Immunosup-

pression with corticosteroid (0.5 mg/kg) resulted in a

gradual improvement in GVHD, which evolved into

chronic GVHD. The patient has been in CR without

additional therapy for 114 months.

Case 2

A 38-year-old woman with lymphoma-type ATLL

achieved CR after 3 cycles of CHOP–VMMV

chemotherapy regimen consisting of CHOP and etoposide,

ranimustine, mitoxantrone, and vindesine [21]. In March

2002, she underwent allo-PBSCT (7.4 9 106 CD34? cells/kg)

from an HLA-matched sibling donor with a myeloablative

regimen of 12 Gy TBI and 120 mg/kg CY (Table 1).

Prophylaxis for GVHD consisted of CSP and MTX. Rapid

engraftment was observed and complete donor-type chi-

merism was documented on day 30. The patient developed

acute, cutaneous GVHD (grade II, stage 3) but responded

well to corticosteroid therapy.

In August 2002, 5 months after allo-PBSCT, subcuta-

neous nodules appeared on the dorsum of her right thigh,

and a biopsy indicated relapse of ATLL. The patient

received chemotherapy that resulted in a remarkable

reduction of the subcutaneous tumors. The first DLI

(1.0 9 107 CD3? cells/kg) was performed using the same

donor; gut GVHD (grade II, stage 1) developed after

22 days but disappeared spontaneously. Subsequently, all

subcutaneous nodules of ATLL disappeared completely.

In December 2002, she presented with progressive

weakness and numbness in both lower limbs due to a mass

lesion in the spinal canal. Examination of cerebrospinal

fluid showed infiltration of abnormal lymphocytes, which

were positive by PCR for HTLV-I. Further systemic

investigation did not detect any ATLL involvement of

other organs. Based on these observations, relapse of

ATLL confined to the central nervous system (CNS) was

diagnosed. Four sessions of intrathecal chemotherapy were

administered, followed by irradiation of the entire brain

and spine. The second DLI (4.3 9 107 CD3? cells/kg) was

performed in February 2003, followed by the third DLI

4 weeks later. No GVHD was observed during or after

DLIs, and the patient obtained the third CR.

In June 2003, the patient developed numbness and

dysesthesia in the left radial region. Imaging showed a

tumor infiltrated to the left brachial plexus, and needle

biopsy of this tumor revealed infiltration of ATLL cells.

Following radiation therapy of the left brachial plexus, the

fourth and fifth DLIs (7.0 9 107 and 5.0 9 107 CD3?

cells/kg, respectively) were performed in mid-July and late

August 2003, and the ATLL lesion disappeared. The total

infused dose of lymphocytes received by this patient in 5

times of DLIs was 21.6 9 107 CD3? cells/kg. Cutaneous

and oral chronic GVHD gradually developed, which were

confirmed by skin biopsy. The patient has remained in CR

for 97 months after the final DLI.

Discussion

Allo-HSCT is only effective at inducing long-term remis-

sion in 30–40 % of patients with aggressive ATLL [7–11].

Previous reports have shown that ATLL patients who

DLI for ATLL 727

123

developed mild acute GVHD following allo-HSCT had a

longer OS compared with those who did not [22, 23].

Interestingly, 4 Japanese groups reported that 14 out of 19

ATLL patients with post-transplant recurrent disease

achieved CR after reduction or discontinuation of immu-

nosuppressants [8, 9, 12, 13]. In addition, generation of

cytotoxic T lymphocytes against ATLL cells can be

induced in some ATL patients after allo-HSCT [24, 25].

These data clearly demonstrate efficacy of graft-versus-

ATLL effects that contribute to improved survival in a

subset of patients. Thus, these findings support the possible

effectiveness of DLI for ATLL relapse following allo-

HSCT, since DLI may further enhance allogeneic immune-

mediated antitumor activity after allo-HSCT [16]. However,

there have been few studies on the efficacy of DLIs for

ATLL relapse.

Besides the 2 cases reported here, only 5 other patients

with ATLL patients have been treated with DLI for post-

transplant relapse of ATLL [7, 9, 13] (Table 2). Kami et al.

[7] reported that 2 patients with post-transplant relapse

(case 3 and 4) received a single DLI after a rapid with-

drawal of CSP. Both patients gained CR, but they died of

exacerbation of the pre-existing chronic GVHD [7].

Yonekura et al. [9] reported that DLIs were administered to

2 patients with persistent ATLL even after cessation of

immunosuppressants. In 1 of these patients (case 5), DLI

failed to induce either graft-versus-ATLL and GVHD,

whereas the other (case 6) obtained CR after once DLI but

Table 2 Donor lymphocyte infusion for ATL

Kamimura (present study) Kami [7] Yonekura [9] Choi [13]

Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7

Age/sex 52/F 38/F 48/F 55/M 51/M 51/F 53/F

Subtype of ATL Lymphoma Lymphoma Chronic Chronic Acute Acute Acute

Conditioning regimen Myeloablative Myeloablative Myeloablative Myeloablative Reduced-

intensity

Reduced-

intensity

Reduced-

intensity

Disease status at

transplant

PR CR CR PD PD PD PR

Disease status after

transplant

CR CR NA NA PR PR CR

Involved organ at

ATL relapse

Skin, PB Skin, CNS, brachial

plexus

NA NA Skin, PB,

LN

Skin, PB,

LN

Skin

Acute GVHD before

DLI

II II I III 0 0 II

Chronic GVHD

before DLI

Yes (limited) No Yes

(extensive)

Yes

(extensive)

NA NA Yes

Donor lymphocyte infusion

(Infused CD3? cells) (9 107/kg)

The first DLI 1.0 1.0 NA NA 14.6 5.26 NA

The second DLI 4.3

The third DLI 4.3

The fourth DLI 7.0

The fifth DLI 5.0

Treatments except

DLI

None Chemotherapy and

irradiation

None None NA None None

Outcome of ATL

after DLI

CR CR CR CR PD CR CR

GVHD after DLI III II NA NA 0 III NA

Chronic GVHD after

DLI

Yes

(extensive)

Yes (limited) Yes

(extensive)

Yes

(extensive)

NE NE NA

Outcome Alive

(114 months)

Alive (97 months) Dead Dead Dead Dead Alive

(54 months)

Cause of death – – Chronic

GVHD

Chronic

GVHD

ATL GVHD –

GVHD graft-versus-host disease, DLI donor lymphocyte infusion, CR complete remission, PR partial response, PD progressive disease, CNScentral nervous system, PB peripheral blood, LN lymph node, NA not available, NE not evaluated

728 T. Kamimura et al.

123

developed severe GVHD that proved fatal. Neither patient

received any chemotherapy. Choi et al. [13] reported that a

single patient (case 7) with relapse of ATLL was treated

with systemic chemotherapy followed by DLI after dis-

continuation of CSP. This patient achieved durable CR for

54 months. Information about the occurrence of GVHD in

this patient following DLI was not provided. In our study,

case 1 was in relapse of ATLL despite the rapid withdrawal

of the immunosuppressants and development of chronic

GVHD after allo-HSCT. The patient had achieved CR after

a single DLI that exacerbated GVHD; this patient has

remained in CR without additional therapy for 114 months

after the DLI. In contrast, case 2 had suffered the repeated

relapses confined to the localized sites such as skin, CNS,

and brachial plexus. For the first relapse in the skin, the

patient was treated with systemic chemotherapy followed

by DLI, but the subsequent relapse in CNS occurred

despite the development of GVHD after the first DLI.

This fact suggests that graft-versus-ATLL effects in the

extrahematopoietic sites might not be as effective as those

in the bone marrow and peripheral blood. The patient was

therefore treated with intrathecal chemotherapy and

radiotherapy of CNS in combination with additional DLIs,

since isolated extrahematopoietic relapse is usually

accompanied by hematologic relapse [26, 27]. However,

the patient suffered the third relapse again in a different

extrahematopoietic site, brachial plexus. The patient was

treated with local irradiation therapy followed by DLIs; the

patient has been in long-term CR for 8 years following the

final DLI.

Cell dose of DLI would be an important factor to induce

graft-versus-ATLL effects while avoid the occurrence of

severe GVHD [16]. Our patients (case 1 and 2) who had

presented GVHD before DLIs, received a total DLIs of

either 1.0 9 107 or 21.6 9 107 CD3? cells/kg. This

exacerbated GVHD in both patients, who have remained in

CR for 8 or 9 years. In contrast, case 6 achieved CR but

died of severe GVHD after DLI of 5.26 9 107/kg CD3?

cells per kg, and case 5 did not respond to high-dose DLI of

14.6 9 107 CD3? cells/kg and died of ATLL progression

without any signs of GVHD.

Based on the small numbers of patients reported thus

far, it is not clear which patients will have a favorable GvL

effect, which will develop significant GVHD after DLI, or

what lymphocyte dose is optimal to induce GvL effects

without significant GVHD. There have been many clinical

studies of DLI in patients in relapse with other hemato-

logical malignancies such as chronic myelogenous leuke-

mia [16, 17], acute myelogenous leukemia [16, 18], and

non-Hodgkin lymphoma [16, 19]. These studies recom-

mend that chemotherapy or radiotherapy administered

prior to DLI play a significant role to maximize the

effectiveness of DLI by reducing tumor burden and that

escalating doses of donor lymphocytes with lower initial

cell doses might separate GvL effect from the lethal

exacerbation of GVHD. Since at least a subset of relapsed

ATLL seem to be susceptible to the GvL effects by DLI,

these recommendations may be useful for the treatment of

this malignancy.

Although numerous studies have reported the favorable

results of allo-HSCT for ATLL, convincing evidence in

support of clinically relevant graft-versus-ATLL responses

has been so far lacking. Our observations and a literature

review have strongly suggested that a positive effect of

DLI on ATLL patients is attributable to graft-versus-ATLL

effect. Further investigations will be necessary to deter-

mine the appropriate administration of DLI for treating

ATLL relapse.

Acknowledgments We thank the nursing staff who cared for the

patients at the Harasanshin Hospital and Kyushu University Hospital.

This work was supported, in part, by a Grant-in-Aid from the Ministry

of Education, Culture, Sports, Science, and Technology in Japan

(23390254 to T.M.).

Conflict of interest The authors declare no conflict of interest.

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