Autologous stem cell transplantation for nasal NK/T-cell lymphoma: a progress report on its value
W. Y. Au1,+,
A. K. W. Lie1,
R. Liang1,
Y.-L. Kwong1,
C.-C. Yau2,
M. M. C. Cheung3,
,
K.-C. Ngan3,
W.-H. Lau3,
K.-H. Wong3,
H.-Y. Yiu3,
H.-C. Cheng3,
K.-H. Au3 and
J. K. C. Chan4
Departments of 1 Medicine and 2 Clinical Oncology, Queen Mary Hospital, Hong Kong; Departments of 3 Radiotherapy and 4 Pathology, Queen Elizabeth Hospital, Hong Kong, Peoples Republic of China
Received 10 February 2003; revised 14 April 2003; accepted 11 August 2003
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Abstract
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Nasal NK/T-cell lymphoma is an EpsteinBarr virus-related, highly aggressive but localized disease in Orientals. The median survival is <1 year. Here, we update our experience on 18 patients treated with autologous stem cell transplantation (ASCT). Two patients died of mucositis and septicemia during ASCT. Relapse occurred in nine cases, including six local relapses. Compared with patients treated in remission, all patients treated in active or disseminated disease died of early relapse. Within this cohort, there was no significant survival difference between patients treated in first (CR1, n = 7) or second (CR2, n = 5) complete remissions. However, among consecutive cases analyzed, the patients receiving ASCT at CR1 showed a trend towards better overall survival compared with historical matched controls (P = 0.064). Disease relapse beyond 6 months was not seen after ASCT. Our retrospective data suggest that ASCT in CR1 is a viable consolidation therapy for local-stage NK/T lymphoma, but a randomized trial is needed to prove any definite survival benefit. For patients with relapsed, refractory or extranasal disease, early consideration for allogeneic transplantation and alternative therapy may be warranted.
Key words: autologous stem cell transplantation, nasal NK/T lymphoma
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Introduction
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The most common type of non-B-cell lymphoma in oriental patients is extranodal natural killer (NK)-cell/T-cell lymphoma [1]. It is characterized by EpsteinBarr virus (EBV) association, angioinvasion and angiodestruction [2]. The disease is rare, and we reported previously two of the largest single-center series with 23 and 50 patients, respectively [2, 3]. The optimal treatment is unknown and the clinical outcome unfavorable. While combination chemotherapy and radiotherapy can produce complete remissions (CRs) in 60% of patients, local or distant relapses are common, giving a long-term survival of 30% [2, 3]. Since high-dose chemotherapy (HDT) and autologous stem cell transplantation (ASCT) gives a survival benefit for localized relapses of diffuse large B-cell lymphoma, it has been used in relapsed nasal NK/T lymphoma with preliminary success [4, 5]. Here, we update our experience with a group of 18 consecutive cases treated over a decade in two institutions.
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Materials and methods
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A diagnosis of lymphoma was confirmed by morphological assessment and immunohistochemical evaluation, and supported by molecular studies as required. The NK lymphoma group was positive for CD3
, CD56 and EBV early RNA (EBER) [1]. The T-cell group was characterized by surface CD3 expression and clonal T-cell receptor gene rearrangement analysis by Southern blot/PCR analysis using frozen tissue [1, 2]. All patients underwent full Ann Arbor staging with total-body computed tomography (CT) scanning and bilateral bone marrow examinations with EBER and CD56 staining [6]. The induction and salvage combination chemotherapy and radiotherapy was heterogeneous, and was clinically decided by the consultant in charge. In-field radiotherapy dosage ranged from 40 to 65 Gy, with or without coning and cisplatinum chemosensitization (Table 1). Remissions and relapses were confirmed by histology and imaging. Cases with clinically quiescent disease but with persistent EBER and CD56+ lymphoma present in nasopharyngeal biopsy or CT evidence of residual lymphoma infiltrates were labeled as partial remissions (PRs).
Patients 13, transplanted with autologous marrow before 1996, have been reported on previously [5]. From 1996, all nasal NK/T-cell lymphoma patients below the age of 65 years, good performance score (Eastern Cooperative Oncology Group 0 or 1) and with chemoresponsive disease were offered HDT with peripheral blood stem cell (PBSC) support at all stages of disease without marrow involvement. A total of seven patients agreed to first remission (CR1) ASCT, and an additional eight cases were transplanted in second remission (CR2) or chemoresponsive active disease. Apart from patient consent, age and medical fitness, there were no exclusion criteria. Non-total-body irradiation (non-TBI) conditioning was used in 17 cases [CBV in 15 (etoposide, carmustine, cyclophosphamide); BEAC in one (carmustine, etoposide, cyclophosphamide, cytosine arabinoside)]. One patient (case 5) received CY-TBI (cyclophosphamide 120 mg/kg, TBI 12 Gy) conditioning. KaplanMeier and log-rank analyses were used for survival analysis (SPSS 10.0; SAS Institute, Chicago, IL, USA). To study any survival advantage of upfront CR1 ASCT, these cases were compared with survival data from 26 consecutive cases of stage I/II nasal NK/T lymphoma below the age of 65 years and achieving CR1, but declining ASCT, during the same time period [2, 7].
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Results
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Patients
The ASCT group included 12 men and six women (median age 41 years, range 2052) (Table 1). This included 16 cases of NK-cell and two cases of T-cell nasal lymphoma (cases 4 and 14). Eight cases were treated in CR1, five in CR2 and five with refractory disease at presentation or relapse [non-remission/partial remission (NR/PR)]. Five patients developed extra-nasal disease (skin, adnexa, liver) without marrow involvement before ASCT. A summary of their clinical details (Table 2) showed that treatment choice may have been influenced by sex and age. As expected, patients who achieve CR before transplantion tend to have more localized disease. Combination chemotherapy and radiotherapy was used as initial treatment, except in cases 3 and 8, which were treated with in-field radiotherapy (40 Gy) at diagnosis. Since most patients received chemotherapy first, the effect of the sequence of treatment (upfront chemotherapy or radiotherapy) could not be analyzed in this small retrospective cohort.
Outcome
Two patients (cases 7 and 14) treated in PR died early (days 23 and 31, respectively) of Gram-positive bacterial sepsis, pneumonia and massive pericardial effusion. Eight patients relapsed between 1 and 6 months. All patients with extra-nasal disease at ASCT died of disseminated disease, with apparent liver predilection. Two-thirds of relapses (six of nine) occurred in the nasal/upper aerodigestive region, and only one patient (case 11) survived after salvage radiotherapy. Seven patients are in continuous CR, including two reported patients at >5 and 10 year follow-up, respectively. Of note, patient 1 had an uneventful pregnancy at 3 years post-ASCT.
Survival analysis
The survival difference between the CR1, CR2 and PR/NR groups is shown in Table 2, and was significantly different in terms of disease-free survival (DFS) (P = 0.0027) and overall survival (OS) (P = 0.0034), mainly because of the poor survival of PR/NR cases. The actuarial survival of the whole cohort plateaued at 39% (±12.4%, standard error) after 6 months. Prolonged survival plateaued at 59% (±15.4%) for patients treated in remission (CR1 + CR2), but was not achieved for patients transplanted in PR/NR (DFS P = 0.0007, OS P = 0.0012) (Figure 1A). Owing to case selection in earlier CR2 ASCT cases, subgroup analysis did not show any significant difference between patients treated in CR1 or CR2 (DFS P = 0.44, OS P = 0.21). The outcome for seven CR1 ASCT cases was further compared with 26 stage I/II nasal NK/T lymphoma cases in CR1 after 1996 (Table 3). Relapse occurred in 22 cases in the control group at a median of 12 months (range 232). Attempted ASCT salvage was performed at relapse or CR2 in five cases, but with no long-term DFS. On actuarial analysis, there was a trend towards improved DFS (P = 0.052) and OS (P = 0.064) for CR1 ASCT (Figure 1B).

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Figure 1. (A) Eighteen cases of autologous stem cell transplantation (ASCT) for NK/T-cell lymphoma. (B) Overall survival of ASCT at first remission compared with cases with no ASCT at first complete remission. Arrows indicate the five cases that underwent ASCT at second complete or partial remission after relapse (see text for details).
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Discussion
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While there are convincing data that ASCT is of survival benefit for relapsed diffuse large B-cell lymphoma, the data for T-cell or NK-cell lineage is scarce. Two large Caucasian SCT series involving 50 cases reported a 3-year survival between 39% and 58%. However, the histology was heterogeneous, involving five different WHO lymphoma categories and >20% of cases were unclassified [8, 9]. Lymphomas of NK- and T-cell lineage constitute 20% of lymphomas in oriental patients, and nasal NK/T-cell lymphoma is the most common entity [3, 10]. With conventional treatment, the median 5-year survival is only 30% [2, 3]. Localized disease, chemoresponsiveness and lack of marrow involvement [6] make ASCT an attractive treatment option.
Our updated and combined series represents the largest ASCT experience for nasal NK/T-cell lymphoma. Several important conclusions can be drawn. First, the updated results in sequential cases look less encouraging than the earlier case reports, reflecting earlier case selection and reporting bias. In particular, ASCT salvage beyond CR1 appeared less applicable and successful than was earlier thought [5]. On the other hand, due to the acceptable therapy-related risks, the high actuarial survival after CR1 ASCT appeared promising. Unlike conventional treatment, relapse was not seen 6 months after ASCT. There was also a trend towards survival advantage for CR1 ASCT compared with historical controls. We must emphasize strongly, however, that this cohort is retrospective, heterogeneous and non-randomized in nature. It is also a small number of cases with relatively short follow-up. The reliability of statistical analysis in such circumstances is bound to be limited. Nevertheless, this still represents the best current treatment results, and the most extensive and comprehensive interim experience for this rare disease entity. Secondly, despite the use of PBSC support, early treatment-related mortality remained a problem: lymphoma-related upper airway angiodestruction and necrosis predispose to aspiration pneumonia and infection. Thirdly, despite the aggressive treatment, recurrent local nasal disease was not uncommon, further underlining the site-predilection of the tumor. Furthermore, even within this small cohort, the disease course was heterogeneous. Salvage of local relapses and occurrence of very late relapses may complicate the analysis of the survival benefit of ASCT. Hence, the utility and proper timing of ASCT can only be addressed by a randomized trial, which would require a large number of participating centers for this rare disease. Finally, ASCT does not seem to alter the dismal prognosis for disseminated disease or early refractory disease. There are several reports of successful treatment of peripheral T-cell lymphomas with allogeneic stem cells [9, 11, 12], even in the syngeneic setting with no graft-versus-host disease for NK lymphoma [13]. This may be attributed to restoration of anti-EBV immunity, and a non-ablative allogeneic SCT may be a therapeutic option.
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Footnotes
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+ Correspondence to: Dr W. Y. Au, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong, Peoples Republic of China. Tel: +852-28554792; Fax: +852-29741165; E-mail: auwing{at}hotmail.com 
W. Y. Au and M. M. C. Cheung contributed equally to the work presented here. 
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