CASE REPORT

Successful treatment of small cell variant anaplastic large celllymphoma with allogeneic peripheral blood stem celltransplantation, and review of the literature

Rie Imamura • Fumihiko Mouri • Kei Nomura • Takayuki Nakamura • Eijiro Oku •

Satoshi Morishige • Yuka Takata • Ritsuko Seki • Koichi Osaki • Michitoshi Hashiguchi •

Koji Yoshimoto • Koichi Ohshima • Koji Nagafuji • Takashi Okamura

Received: 31 August 2012 / Revised: 4 December 2012 / Accepted: 4 December 2012 / Published online: 20 December 2012

� The Japanese Society of Hematology 2012

Abstract The small cell variant of anaplastic large cell

lymphoma (ALCL) presents in a nearly identical manner to

the more common ALK? primary ALCL, with the exception

that it is more frequently associated with leukemic involve-

ment, and the prognosis has been reported to be poor. We

report a 40-year-old Japanese male who was diagnosed with

small cell variant ALCL with peripheral blood involvement

stage IVB, age-adjusted international prognostic index 3.

Conventional cytogenetics of the bone marrow aspirate

specimen showed abnormal metaphases with the following

karyotype: 47, XY, ?X, t(2;5)(p23;q35). The patient was

treated with acute lymphoblastic leukemia-oriented intensive

chemotherapy. He underwent allogeneic peripheral blood

stem cell transplantation from his HLA-DR1 locus mismatch

sister. Prior to transplant, the patient had residual lymphad-

enopathy considered to be in partial remission. As of August

2012, the patient has achieved 18 months of continuous

complete remission (CCR), with a Karnofsky score of 100 %.

We have identified a total of seven cases of small cell variant

ALCL treated with allogeneic hematopoietic stem cell

transplantation (HSCT) in the literature. Of these, no relapse

was reported, and four patients were CCR more than 1 year.

Allogeneic HSCT appears to represent a promising treatment

option for small cell variant ALCL.

Keywords Anaplastic large cell lymphoma � Small cell

variant � ALK � Allogeneic � Transplantation

Introduction

Anaplastic large cell lymphoma (ALCL), a subgroup of

non-Hodgkin’s lymphoma with expression of CD30 (Ki-1),

was first described in 1985 by Stein et al. [1]. Anaplastic

lymphoma kinase (ALK) expression exists in approxi-

mately 60 % of ALCL cases [2]. Compared with the ALK-

negative cases, ALK-positive cases are usually character-

ized by younger age, an advanced stage, more systemic

symptoms, more extranodal involvement at presentation, a

good response to chemotherapy, and a good prognosis

[3, 4].

Among subentities of ALCL, small cell variant was first

reported by Kinney et al. [5] in 1993. The small cell variant

of ALCL presents nearly identically to the ALK-positive

primary ALCL, with the exception that leukemic involve-

ment has been more commonly described in the small cell

variant [6]. The prognosis of small cell variant of ALCL

has been reported to be poor [5, 7, 8].

Here, we report a case of small cell variant ALCL

successfully treated with allogeneic peripheral blood stem

cell transplantation, and review the literature on allogeneic

hematopoietic stem cell transplantation (HSCT) for small

cell variant ALCL.

Case report

A 40-year-old Japanese male was admitted to our hospital

because of fever, lymphadenopathy, and elevated white

blood cell count without body weight loss or night sweat in

R. Imamura � F. Mouri � K. Nomura � T. Nakamura � E. Oku �S. Morishige � Y. Takata � R. Seki � K. Osaki �M. Hashiguchi � K. Yoshimoto � K. Nagafuji (&) � T. Okamura

Division of Hematology and Oncology,

Department of Medicine, Kurume University School

of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan

e-mail: knagafuji@med.kurume-u.ac.jp

K. Ohshima

Department of Pathology, Kurume University School

of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan

123

Int J Hematol (2013) 97:139–143

DOI 10.1007/s12185-012-1242-3

October 2010. His performance status was 2. Physical

examination revealed enlarged left cervical, bilateral axil-

lary, and bilateral inguinal lymphadenopathy with hepato-

splenomegaly. Imaging study revealed bilateral pleural

effusion. A complete blood count showed leukocytosis of

34.0 9 109/L with 31 % abnormal lymphoid cells consist-

ing of a mixture of small, markedly atypical lymphoid cells

and large lymphoma cells. These cells were basophilic and

had variations in size and nuclear shape, and some cells had

vacuolated cytoplasm (Fig. 1). The serum lactate dehy-

drogenase concentration was 1910 IU/l (normal range

119–229 IU/l), and the serum soluble interleukin-2 receptor

concentration was markedly elevated to 147015 U/ml

(normal range \466 U/ml). Bone marrow aspiration and

biopsy revealed hypercellular marrow with 10 % abnormal

lymphoid cells (Fig. 2a). Immunohistochemistry performed

on the bone marrow aspirate clot specimen showed that the

cells were positive for ALK-1, CD30, and EMA. The CD30

pattern of expression was membranous and paranuclear

(Fig. 2b). The pattern of ALK-1 was nuclear and cyto-

plasmic (Fig. 2c). Flow cytometric analysis showed

abnormal population of cells positive for CD2, cytoplasmic

CD3, CD4, CD7, CD25, CD30, and negative for CD8,

CD56, CD16, CD20, cytoplasmic CD79a, myeloperoxi-

dase, CD34, TdT. Conventional cytogenetics of the bone

marrow aspirate specimen showed 3 normal and 17

abnormal metaphases with the following karyotype: 47,

XY, ?X, t(2;5)(p23;q35). Fluorescence in situ hybridiza-

tion showed disruption of the ALK gene on 2p23. The

patient was diagnosed with ALK-positive ALCL small cell

variant with leukemic peripheral blood involvement, stage

IVB, with age-adjusted international prognostic index

(AA-IPI) 3. The patient received induction chemotherapy

for acute lymphoblastic leukemia (ALL). The patient

achieved hematologic complete remission with partial

remission (PR) status of lymphadenopathy, while menin-

geal invasion developed at the end of induction therapy. The

analysis of cerebrospinal fluid revealed increased

Fig. 1 Peripheral blood smear (91000) showing many small-/

intermediate-sized atypical lymphoid cells and large and atypical

lymphoid cells with basophilic and vacuolated cytoplasm

Fig. 2 a Bone marrow biopsy revealed hypercellular marrow with

10 % abnormal lymphoid cells (9400). b The large cells expressed

CD30 antigen in a cytoplasmic membrane and Golgi distribution

(9400). c The large cells expressed ALK in a cytoplasm and nucleus

distribution (9400)

140 R. Imamura et al.

123

concentration of protein (125 mg/dl) and cell numbers

(26 9 106/L) showing atypical cells consisted with lym-

phoma. Central nervous system (CNS) invasion was suc-

cessfully treated with intrathecal methotrexate in addition to

high-dose methotrexate and high-dose cytarabine. After

three courses of consolidation therapy, the patient under-

went allogeneic peripheral blood stem cell transplantation

from his HLA-DR 1 locus mismatch sister in February

2011. The interval from initial diagnosis to transplant was

5 months. Prior to transplant, the patient had residual

lymphadenopathy considered to be PR status while the bone

marrow examination revealed no residual lymphoma cells.

The patient then received a conditioning regimen con-

sisting of total body irradiation (12 Gy in 6 fractions on days

-8 to -6), etoposide (12.5 mg/kg on days -5 to -4), and

cyclophosphamide (60 mg/kg on days -3 to -2) [9]. The

numbers of infused cells and CD34 positive cells were

30.4 9 107/kg and 4.1 9 106/kg, respectively. Graft-ver-

sus-host disease (GVHD) prophylaxis consisted of intrave-

nous cyclosporin (3 mg/kg/day) beginning on day -1 and

short-term methotrexate on days 1 (10 mg/m2), 3 (7 mg/

m2), 6 (7 mg/m2), and 11 (7 mg/m2). Rapid engraftment was

obtained. A neutrophil count [0.5 9 109/L and a platelet

count [20 9 109/L were achieved on days 10 and 15,

respectively, and complete donor chimerism was observed

in a bone marrow sample on day 28. Grade II acute GVHD

that developed was successfully treated with 2 mg/kg of

methyl-prednisolone. CT scan on day 40 revealed complete

disappearance of lymphadenopathy. As of August 2012, the

patient had achieved 18 months of continuous complete

remission (CCR) with Karnofsky score of 100 % (Fig. 3).

Discussion

In 1995, Shiota et al. [3] first reported that ALK-positive

ALCL patients have a better prognosis than those who are

ALK-negative, reporting 5-year overall survival (OS) of

79.8 versus 32.9 %. This observation was confirmed in 2

large series of ALCL patients [2, 10]. Thus, anthracycline-

based chemotherapy is recommended for the initial treat-

ment for ALK-positive ALCL patients. Good prognosis

patients (AA-IPI 0–1) had a 10-year OS of 94 % com-

pared with 41 % in patients with AA-IPI 2–3 [2]. Prog-

nosis is so good in this group of patients that autologous

HSCT should only be considered in case of relapse. ALCL

patients autografted at relapse have a 78–100 % 3-year OS

[11–13].

Small cell variant ALCL, first reported by Kinney et al.

[5] in 1993, is characterized by a mixture of small, medium-

sized, and large anaplastic cells positive for CD30 and ALK

[14]. Most patients are young at presentation, with a median

age of 14 years (range 4 months–40 years). Sites of

involvement frequently include peripheral blood, peripheral

lymph nodes, and skin. Most patients present with consti-

tutional symptoms, often with stage III/IV. The prognosis

of small cell variant ALCL has been reported to be poor

[5, 7, 8]. ALCL99 study analyzed 375 child patients with

ALK-positive ALCL. Among them, 22 patients (6 %) were

classified as small cell variant, and the hazard ratio for

failure was 4.7 (95 % CI 2.6–8.5) in patients with small

cell ALCL relative to the common type [15]. Indeed,

ALK-positive ALCL with leukemic involvement, most of

which cases are small cell variant, is reported to be a

0

500

1000

1500

2000Induction HD-

AraCHD-MTX

Abnormal cell 10.0% 0% 0% 0%

t(2;5) 85%46,XY 15%

Karyotype 46,XY 100%

46,XY 100%

XY-FISH XX 99.6%

IT MTX

Bone Marrow

TBI/VP16/CY

AllogeneicPBSCT

CSF cell count 26/µL 3/µL 0/µL

LDH

sIL2R147015 U/ml 755 U/ml 1522 U/ml 527 U/ml 765 U/ml 677 U/ml

LDH ( U/L )

HD-AraC

Oct.2010 Nov. Dec. Jan. 2011 Feb. Mar.

0%

IT MTX IT MTXFig. 3 Clinical course. HDhigh-dose, AraC cytarabine,

MTX methotrexate, CSFcerebrospinal fluid, TBI total

body irradiation, VP-16etoposide, CYcyclophosphamide, PBSCTperipheral blood stem cell

transplantation

Successful treatment of small cell variant ALCL 141

123

clinicopathologic entity with an unfavorable prognosis [8].

This proposal was supported by Nguyen et al. [16]. The

authors reviewed 21 cases of ALCL with leukemic pre-

sentation: of these, 18 were small cell variant, and 13 of

them died of the disease, usually within a few months, and

only one case had CCR after completion of chemotherapy.

Our patient was diagnosed with ALK-positive ALCL

small cell variant with leukemic peripheral blood

involvement, and was treated aggressively with ALL-

directed chemotherapy, resulting in PR status. Meningeal

infiltration was successfully treated with systemic and

intrathecal chemotherapy. Because of reported poor prog-

nosis of small cell variant ALCL with leukemic presenta-

tion, the patient was preceded to allogeneic PBSCT from

HLA-DR 1 locus mismatched related donor, and has since

been enjoying over 18 months CCR.

The role of allogeneic HSCT for ALCL has been eval-

uated in several reports. Berlin-Frankfurt-Munster group

reported 20 children and adolescents with high-risk relapsed

or refractory ALCL who underwent allogeneic HSCT, with

disease status at transplantation of 12 complete remission

(CR), 3 PR, 3 active disease, and 2 not evaluable. Three-

year event-free survival (EFS) was 75 ± 10 % [17].

Societe Francaise de Greffe de Moelle et de Therapie

Cellulaire reported a retrospective analysis including 27

adult ALCL patients who underwent allogeneic HSCT, with

disease status at transplantation of 10 CR, 6 PR, and 11

stable disease (SD)/progressive disease (PD). The 5-year

OS was 55 % (95 % CI 35–72 %) [18]. Dodero et al. [19]

reported 11 cases of reduced-intensity conditioning

allogeneic HSCT for relapsed ALCL, with 5-year OS 54 %

(95 % CI 23–70 %).

These data clearly show that allogeneic HSCT is an

effective therapy for advanced ALCL, suggesting a graft-

versus-ALCL effect. However, because of a lack of

detailed pathological information, we cannot identify cases

of small cell variant ALCL in these reports.

We have identified a total of 7 cases of small cell variant

ALCL treated with allogeneic HSCT, presented in Table 1

[8, 16, 20–22]. Disease status prior to transplantation was 1

1CR, 1 2CR, 2 1PR, 2 refractory. Among them, no relapse

was reported, and 4 patients were CCR more than 1 year.

Thus, allogeneic HSCT seems to be a promising treatment

option for small cell variant ALCL.

In conclusion, we report a small cell variant ALK-

positive ALCL adult patient with disease status 1PR suc-

cessfully treated with allogeneic HSCT. Because of lack of

more detailed information, there is a possibility that some

reports of allogeneic HSCT for ALCL might include cases

of small cell variant ALCL. More accumulation of case

records would help to evaluate the role of allogeneic HSCT

for small cell variant ALCL.

Conflict of interest None.

References

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Table 1 Reported cases of allogeneic hematopoietic stem cell transplantation for small cell variant anaplastic large cell lymphoma

Patient Age/sex Primary location WBC count

(9109/L)

Lymphoma

cell in PB (%)

Disease status at

transplantation

Transplantation Follow-up References

1 18/F LN, skin, BM 15 54 2CR R-SCT CCR

18 months

7

2 20 months/F LN, BM, liver,

spleen

37.9 65 1 relapse R-SCT Died within

few months

7

3 6/F Lung, kidney, BM 204 51 Primary

refractory

Haplo-SCT CCR

17 months

15

4 16/M LN, lung, skin,

liver, spleen

NA NA 1CR U-BMT CCR

39 months

19

5 29/M LN, BM, liver,

spleen, pleura,

CNS

47.9 19 1PR U-BMT Died of

GVHD

1 month

20

6 23/F LN, BM, liver,

spleen, pleura,

skin

24.5 5.5 1 relapse HSCT Unknown 21

7 40/M LN, BM, liver,

spleen, pleura

34 31 1PR R-PBSCT CCR

18 months

This case

report

LN lymph node, BM bone marrow, CNS central nervous system, WBC white blood cell, PB peripheral blood, CR complete remission, PR partial

remission, R-SCT stem cell tranplatation from related donor, haplo-SCT SCT from haploidentical related donor, U-BMT bone marrow trans-

plantation from unrelated donor, HSCT hematopoietic stem cell transplantation, R-PBSCT peripheral blood stem cell transplantation from related

donor, CCR continuous complete remission, GVHD graft-versus-host disease

142 R. Imamura et al.

123

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