Volume 14, Issue 12 , Pages 1356-1364, December 2008
Autologous Hematopoietic Stem Cell Transplantation in Extranodal Natural Killer/T Cell Lymphoma: A Multinational, Multicenter, Matched Controlled Study
Article Outline
Abstract
Extranodal natural killer (NK)/T cell lymphoma, nasal type, is a recently recognized distinct entity and the most common type of non–B cell extranodal lymphoma in Asia. This retrospective analysis studied the potential survival benefits of hematopoeitic stem cell transplantation (HSCT) compared with a historical control group. A total of 47 patients from 3 previously published series of HSCT were matched according to NK/T cell lymphoma International Prognostic Index (NKIPI) risk groups and disease status at transplantation with 107 patients from a historical control group for analysis. After a median follow-up of 116.5 months, the median survival time was not determined for the HSCT group, but it was 43.5 months for the control group (95% confidence interval [CI] = 6.7 to 80.3 months; P = .127, log-rank test). In patients who were in complete remission (CR) at the time of HSCT or at surveillance after remission, disease-specific survival rates were significantly higher in the HSCT group compared with the control group (disease-specific 5-year survival rate, 87.3% for HSCT vs 67.8% for non-HSCT; P = .027). In contrast, in subgroup analysis on non-CR patients at the time of HSCT or non-HSCT treatment, disease-specific survival rates were not significantly prolonged in the HSCT group compared with the control group (1-year survival rate, 66.7% for HSCT vs 28.6% for non-HSCT; P = .141). The impact of HSCT on the survival of all patients was significantly retained at the multivariate level with a 2.1-fold (95% CI =1.2- to 3.7-fold) reduced risk of death (P = .006). HSCT seems to confer a survival benefit in patients who attained CR on postremission consolidation therapy. These findings suggest that, in particular, patients in CR with high NKIPI risk scores at diagnosis should receive full consideration for HSCT.
Key Words: NK/T-cell lymphoma, autologous hematopoietic stem cell transplantation, chemotherapy
Extranodal natural killer (NK)/T cell lymphoma, nasal type, is a recently recognized distinct entity in the World Health Organization (WHO) classification of lymphoid tumors [1]. This lymphoma occurs more frequently in Asia than in Western countries and is the most common type of non–B cell extranodal lymphoma in Asia [2]. The treatment outcome for NK/T cell lymphomas depends on disease stage. Overall, long-term survival in these lymphomas, reported as 30% to 40% 3, 4, 5, 6, tends to be inferior to that for other aggressive lymphomas. Even in localized NK/T cell lymphomas, primary chemotherapy and/or radiotherapy (RT) results in complete remission (CR) rates of 40% to 60%, with 5-year overall survival (OS) rates of 42% to 83% 3, 4, 7, 8, 9, 10, 11, with high systemic failure rates of 25% to 30% 7, 8, 9, 12.
In an effort to identify strategies for improving these low success rates in treating NK/T cell lymphoma, the use of high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (HSCT) has been investigated 13, 14, 15, 16, 17. Determining the survival benefit of HSCT based on the results of these studies is difficult, however, because of the small size as well as the heterogeneous nature of the patient cohorts.
Recently, a prognostic model specific for NK/T cell lymphoma (NK/T cell lymphoma International Prognostic Index [NKIPI]) has been proposed and validated 6, 18. Clinical variables included in the NKIPI risk scoring system are B symptoms, stage, lactic dehydrogenase (LDH) level, and regional lymphadenopathies. Owing to its extranodal characteristics, the prognostic impact of the IPI has been controversial in this particular subtype of non-Hodgkin lymphoma (NHL). Similar to other prognostic models, the NK-IPI has the major aim of identifying high-risk patients and thereby provide better risk-based stratification for optimal treatment.
To explore the potential benefits of autologous HSCT, we have pooled and reanalyzed data from 3 previously published series 6, 13, 14. To critically evaluate the role of autologous HSCT, we compared those results with those for a matched control group identified from historical data.
Patients and Methods
Patients and Data Collection
Our cohort comprises 59 patients with NK/T cell lymphomas who underwent autologous HSCT reported in 3 previous studies from Korea, Hong Kong, and Japan 6, 13, 14. From these 59 patients, 48 were selected for reanalysis (Korea, n = 16 [6]; Hong Kong, n = 16 [13]; Japan, n = 16 [14]). Patient selection was based on availability from a historical control group of patients who were matched according to NKIPI risk group (risk score 0-1 vs 2-4) and disease status at transplantation (first CR [CR1], second CR [CR2] vs partial remission [PR]/no response [NR]), at a ratio of 1:3. In cases where the NKIPI score was not available at the time of analysis, only disease status was considered for matching criteria. The sources of the matching control group were the lymphoma data registry for each study group. The order of priority in selection criteria for matched control cases was NKIPI risk score, followed by disease status at transplantation or conventional treatment/observation. The matched control cases (n = 107) received conventional chemotherapy with or without RT (n = 34), RT alone (n = 5) as salvage therapy, or observation (n = 68) at CR1 or CR2 as postremission care instead of HDC/autologous HSCT. All patients had pathologically confirmed NK/T cell lymphoma according to the WHO classification [1]. One patient with negative Epstein-Barr virus (EBV) in situ hybridization from the HSCT group was excluded from the final analysis; thus, the group from Japan included 15 patients.
Extranasal NK/T cell lymphoma was defined as described previously [3]. In brief, upper aerodigestive tract NK/T cell lymphoma (UNKTL) was defined as that involving the nasal cavity, nasopharynx, and the upper aerodigestive tract, whereas extra-upper aerodigestive tract NK/T cell lymphoma (EUNKTL) included lymphomas occurring at all other sites [3]. The following clinical data were collected from the medical records: demographic information, LDH level at diagnosis, initial Ann Arbor stage, IPI at diagnosis, NKIPI at diagnosis, presence or absence of B symptoms, performance status, date of diagnosis, date of autologous HSCT, disease status at transplantation, transplantation outcome, salvage treatment type and outcome, date of last follow-up, and cause of death. The study design was approved by the Samsung Medical Center's Institutional Review Board.
Chemotherapy
Each patient received 1 of the following initial treatment modalities: (1) an anthracycline-containing chemotherapeutic regimen with or without RT (n = 125), (2) a non–anthracycline-containing chemotherapeutic regimen with or without RT (n = 15), (3) involved-field RT (IFRT) as the primary treatment (n = 13), or (4) surgery plus RT (n = 1). Anthracycline-based regimens used included CHOP (cyclophosphamide, (Cy) doxorubicin, vincristine, and prednisolone; n = 68), dose-escalated CHOP (deCHOP; n = 1), velCHOP (velcade plus CHOP; n = 1), CEOP (Cy, epirubicin, vincristine, and prednisolone; n = 14), CEOP/ProMACE (CEOP followed by Cy, doxorubicin, etoposide, and prednisone; n = 4), MACOP B (methotrexate [MTX], doxorubicin, Cy, vincristine, prednisone, and bleomycin; n = 2), CHOEP (Cy, doxorubicin, vincristine, etoposide, and prednisolone; n = 6), ProMace (n = 3), ProMace/Cytabom (ProMace plus cytabarabine, bleomycin, vincristine, MTX, and leucovorin; n = 21), COPBLAM (Cy, vincristine, prednisone, bleomycin, doxorubicin, and procarbazine; n = 2), EPOCH (etoposide, doxorubicin, vincristine, Cy, and prednisolone; n = 1), cisplatin/Cy/adriamycin/vindesine/prednisolone (n = 1), and epi-COP (epirubicin, Cy, vincristine, prednisolone; n = 1). The non–anthracycline-containing regimens used were IMEP (ifosfamide, MTX, and etoposide; n = 3), ESHAP (etoposide, methylprednisolone, cisplatin, and cytarabine; n = 1), DHAP (dexamethasone, cytarabine, and cisplatin; n = 1), DeVIC (carboplatin, etoposide, ifosfamide, and dextamethasone; n = 1), IMVP-16 (ifosfamide, MTX, and etoposide; n = 2), and VIPD (etoposide, ifosfamide, cisplatin, and dexamethasone; n = 7). In patients with localized disease, IFRT was given at the physician's discretion after chemotherapy. Treatment response was assessed according to standard response criteria [19].
HDC/Autologous HSCT
The procedures for HDC and autologous HSCT have been described previously 13, 14, 20. In brief, the following conditioning regimens were used: CBV (etoposide, carmustine, and Cy; n = 14), BEAM (carmustine, etoposide, cytarabine, and melphalan (Mel); n = 12), MCEC (ranimustine, Cy, etoposide and carboplatin; n = 8), BEAC (carmustine, etoposide, cytarabine, and Cy; n = 2), Cy/TBI (Cy and total body irradiation; n = 2), VCT (etoposide, Cy and TBI; n = 2), and others (n = 7).
Statistical Analysis
Disease-specific survival and relapse-free survival (RFS) were estimated using the Kaplan-Meier method. Disease-specific survival was calculated from the date of diagnosis to the date of death from the disease or the last follow-up. RFS was calculated from the date of CR to the first documented relapse in patients who attained CR. Survival rates were compared for statistical differences using log-rank analysis. Survival rates were compared for statistical differences by using log-rank analysis. Continuous biological variables were dichotomized for log-rank analysis. A backward-stepwise Cox regression analysis was performed to delineate prognostic factors at the multivariate level, and all hazard ratios (HRs) were adjusted for age. P values < .05 were considered statistically significant, and all P values correspond to 2-sided significance tests.
Results
Patient Characteristics
A total of 47 patients who underwent autologous HSCT were compared with 107 matched controlled cases. Baseline characteristics are summarized in Table 1. All clinical parameters except age and initial Ann Arbor stage were relatively well balanced between the control group and the study group. The median time from diagnosis to transplantation was 8.8 months (range, 2.1 to 86.3 months). The proportion of patients under age 60 years was significantly higher in the autologous HSCT group compared with the control group (95.7% in the autologous HSCT group vs 72.0% in the control group; P = .001). In addition, the proportion of patients with localized disease was lower in the autologous HSCT group (66.0%) than in the non-HSCT group (82.2%) (P = .038). Otherwise, there were no significant differences in distributions of sex, performance status, LDH level, IPI risk group, presence of B symptoms, anatomic category, NKIPI risk group, or primary treatment modality between the 2 groups.
Table 1. Patient and Treatment Characteristics
| All Patients | HSCT | Controls | P Value | |
|---|---|---|---|---|
| Total cases, n (%) | 154 (100) | 47 (30.5) | 107 (69.5) | |
| Median age, years (range) | 47 (17 to 80) | 42 (17 to 62) | 52 (17 to 80) | |
| Age, years, n (%) | ||||
 ≤ 60 | 122 (79.2) | 45 (95.7) | 77 (72.0) | .001 |
| > 60 | 32 (20.8) | 2 (4.3) | 30 (28.0) | |
| Sex, n (%) | ||||
| Male | 111 (72.1) | 34 (72.3) | 77 (72.0) | .962 |
| Female | 43 (27.9) | 13 (27.7) | 30 (28.0) | |
| Performance status, n (%) | ||||
| ECOG 0-1 | 139 (90.3) | 43 (91.5) | 96 (89.7) | .733 |
| ECOG 2-4 | 15 (9.7) | 4 (8.5) | 11 (10.3) | |
| Ann Arbor stage, n (%) | ||||
| Limited (I-II) | 118 (77.1) | 31 (66.0) | 87 (82.2) | .038 |
| Advanced (III-IV) | 36 (23.5) | 16 (34.0) | 20 (17.8) | |
| LDH (n = 150), n (%) | ||||
| ≤ Upper limit of normal | 77 (51.3) | 23 (51.1) | 54 (51.4) | .972 |
| > Upper limit of normal | 73 (48.7) | 22 (48.9) | 51 (48.6) | |
| IPI risk group (n = 151), (%) | ||||
| Low/low-intermediate | 127 (84.1) | 37 (82.2) | 90 (84.9) | .680 |
| High-intermediate/high | 24 (15.9) | 8 (17.8) | 16 (15.1) | |
| B symptoms, n (%) | ||||
| Positive | 97 (63.0) | 27 (57.4) | 70 (65.4) | .345 |
| Negative | 57 (37.0) | 20 (42.6) | 37 (34.6) | |
| Anatomic category, n (%) | ||||
| UNKTL | 141 (91.6) | 42 (89.4) | 99 (92.5) | .516 |
| EUNKTL | 13 (8.4) | 5 (10.6) | 8 (7.5) | |
| NKIPI risk group (n = 145), n (%) | ||||
| Low risk (group 1-2) | 80 (55.2) | 23 (54.8) | 57 (55.3) | .949 |
| High risk (group 3-4) | 65 (44.8) | 19 (45.2) | 46 (44.7) | |
| Primary treatment, n (%) | ||||
| Anthracycline-based chemotherapy ± RT | 125 (81.2) | 41 (87.2) | 84 (78.5) | |
| Non-anthracycline-based chemotherapy ± RT | 15 (9.7) | 3 (6.4) | 12 (11.9) | .600 |
| RT only | 13 (8.4) | 3 (6.4) | 10 (10.2) | |
| Surgical excision + RT | 1 (0.6) | 0 (0.0) | 1 (0.8) | |
| Disease status at treatment, n (%) | ||||
| CR1 | 61 (39.6) | 14 (29.8) | 47 (43.9) | |
| CR2 | 34 (22.1) | 13 (27.7) | 21 (19.6) | .232 |
| PR/NR/PD | 59 (38.3) | 20 (42.6) | 39 (36.4) |
Autologous HSCT Outcome
More than 90% of the patients in each group received primary chemotherapy with or without IFRT (Table 1). Approximately 2/3 of the patients received CBV, BEAM, or MCEC as the conditioning regimen before HSCT. Of the HSCT group, 30% (n = 14) were in CR1, 28% (n = 13) were in CR2, 28% (n = 13) were in PR/SD, and 15% (n = 7) were in PD at the time of transplantation. Using an intent-to-treat analysis, 66.0% (n = 31) attained CR after HSCT, 4.3% (n = 2) attained PR, and 19.1% (n = 9) had PD. Four fatal toxicities were observed, with a treatment-related mortality (TRM) rate of 8.5% (septic shock, n = 1; pneumonia, n = 1; unspecified, n = 2). Of the 31 patients who attained CR after HSCT, 13 (41.9%) experienced relapse; the median RFS from the date of CR to the first documented relapse or follow-up was 23.3 months (range, 0.2 to 180.3 months). Of the 13 patients who experienced relapse, 5 received salvage chemotherapy, 4 received RT, 2 underwent allogeneic HSCT, and 2 received palliative treatment. After a median follow-up of 99.8 months post-HSCT (range, 23.4 to 180.9 months), the median survival time after HSCT has not yet been reached. There was no significant difference in survival between the HSCT and control groups (56.2% vs 47.6%; P = .127) (Figure 1B).
Figure 1
Survival of all patients (A) and survival according to HSCT (B).
Prognostic Analysis for Autologous HSCT
The following clinical factors predicted poor survival of patients undergoing autologous HSCT in univariate analysis: advanced Ann Arbor stage (stage III/IV; P = .045) and disease status at the time of transplantation (non-CR; P <.001) (Table 2). For RFS after autologous HSCT, advanced Ann Arbor stage (stage III/IV; P = .021), elevated LDH level (P = .026), non-CR at the time of transplantation (P = .001), and high IPI risk group (high-intermediate/high; P = .005) predicted relapse after HSCT. In multivariate analysis with stage, the presence of B symptoms, anatomic category, and disease status at HSCT, only disease status at HSCT retained its statistical significance for RFS (P <.001; HR = 3.5; 95% confidence interval [CI] = 1.6 to 7.9) and disease-specific survival (P <.001; HR = 7.2; 95% CI = 4.4 to 1.6). Thus, disease status at autologous HSCT was the most important prognostic factor for survival and RFS.
Table 2. Univariate Analysis for the Patients with HSCT
| Relapse-Free Survival | Disease-Specific Survival | |||
|---|---|---|---|---|
| Parameters | Median (95% CI), Months | P Value | Median (95% CI), Months | P Value |
| Age, years | ||||
| ≤ 60 | 13.7 (0.0 to 30.8) | .600 | NA | NA |
| > 60 | NA | |||
| Ann Arbor stage | ||||
| Limited (I/II) | NR | .021 | NR | .045 |
| Advanced (III/IV) | 4.2 (0.0 to 9.3) | 36.5 (11.0 -62.0) | ||
| LDH | ||||
| ≤ Upper limit of normal | NR | .026 | NR | .145 |
| > Upper limit of normal | 6.2 (0.0 to 29.8) | 31.8 (0.0 to 104.4) | ||
| B symptoms | ||||
| Positive | 16.8 (0.0 to 44.4) | .654 | NR | .536 |
| Negative | 19.3 (0.0 to 43.6) | NR | ||
| Anatomic category | ||||
| UNKTL | 16.8 (0.0 to 34.6) | .527 | NR | .152 |
| EUNKTL | 2.2 (1.3 to 3.2) | 36.5 (0.0 to 73.5) | ||
| Disease status at HSCT | ||||
| CR | NR | .001 | NR | <.001 |
| Non-CR | 2.5 (1.7 to 3.4) | 19.2 (0.0 to 56.5) | ||
| IPI risk group | ||||
| Low/low-intermediate | 21.0 | .005 | NR | .223 |
| High-intermediate/high | 1.8 (1.2 to 2.4) | 19.2 (0.0 to 81.0) | ||
| NKIPI risk group | ||||
| Low risk (group 1-2) | NR | .086 | NR | .066 |
| High risk (group 3-4) | 6.2 (0.0 to 20.1) | 31.1 (0.0 to 70.7) | ||
Impact of HSCT on Survival in NK/T Cell Lymphoma
After a median follow-up of 116.5 months (range, 13.2 to 234.0 months), the median survival was 47.3 months (95% CI = 12.7 to 81.8) for all patients (Figure 1A). The median survival time had not yet been reached for the HSCT group, but it was 43.5 months for the control group (95% CI = 6.7 to 80.3 months; P = .127, log-rank test) (Figure 1B). For all patients in both groups, the clinical factors significantly predicting unfavorable survival in univariate analysis were performance status (Eastern Cooperative Oncology Group [ECOG] 2 to 4; P = .042), advanced Ann Arbor stage (stage III/IV; P = .02), elevated LDH level (P = .010), anatomic category (EUNKTL; P = .017), disease status at treatment (non-CR; P < .001), IPI (high-intermediate/high; P = .027), and NKIPI (group 3-4; P = .003) (Table 3).
Table 3. Univariate Analyses for Disease-Specific Survival of All Patients
| Parameter | Median (95% CI), Months | P Value |
|---|---|---|
| Age, years | ||
| ≤ 60 | 62.4 (22.6 to 102.2) | .901 |
| > 60 | 33.5 (19.5 to 42.4) | |
| Performance status | ||
| ECOG 0-1 | 66.8 (7.4 to 87.2) | .042 |
| ECOG 2-4 | 36.5 (0.0 to 77.2) | |
| Ann Arbor stage | ||
| Limited (I/II) | NR | .002 |
| Advanced (III/IV) | 25.0 (3.2 to 46.9) | |
| LDH | ||
| ≤ Upper limit of normal | NR | .010 |
| > Upper limit of normal | 31.1 (6.6 to 55.5) | |
| B symptoms | ||
| Positive | 36.7 (0.0 to 78.1) | .631 |
| Negative | 66.8 (21.1 to 112.6) | |
| Anatomic category | ||
| UNKTL | 78.8 (42.1 to 115.4) | .017 |
| EUNKTL | 19.2 (10.1 to 28.4) | |
| HSCT | ||
| Yes | NR | .127 |
| No | 43.5 (6.7 to 80.3) | |
| Disease status at HSCT or chemotherapy | ||
| CR | NR | <.001 |
| Non-CR | 10.8 (8.0 to 13.7) | |
| IPI risk group | ||
| Low/low-intermediate | 79.6 (20.2 to 104.6) | .027 |
| High-intermediate/high | 25.0 (0.2 to 49.9) | |
| NKIPI risk group | ||
| Low risk (group 1-2) | NR | .003 |
| High risk (group 3-4) | 30.9 (10.5 to 51.3) |
Clinical parameters included in the multivariate analysis were performance status (0 to 1 vs ≥ 2), Ann Arbor stage (I/II vs III/IV), LDH level (normal vs elevated), anatomic category (UNKTL vs EUNKTL), disease status at treatment (CR1/CR2 vs non-CR), and HSCT versus non-HSCT. A backward-conditional Cox regression model was used. Significant prognostic factors for survival in all patients were LDH level (P = .005; HR = 2.0; 95% CI = 1.2 to 3.2), disease status at treatment (P = < .001; HR = 7.8; 95% CI = 4.6 to 13.0), and HSCT (P = .006; HR = 2.1; 95% CI = 1.2 to 3.7) (Table 4).
Table 4. Multivariate Analysis for Disease-Specific Survival of All Patients
| Parameters | Relative Risk | 95% CI | P value |
|---|---|---|---|
| Performance status: ECOG 0-1 versus 2-4 | 0.6 | 0.3 to 1.4 | .233 |
| Ann Arbor stage: I/II versus III/IV | 1.6 | 0.9 to 2.8 | .129 |
| LDH: ≤ Upper limit of normal versus > upper limit of normal | 2.0 | 1.2 to 3.2 | .005 |
| Anatomic category: UNKTL versus EUNKTL | 1.4 | 0.6 to 3.0 | .457 |
| Disease status at HSCT or chemotherapy: CR versus non-CR | 7.8 | 4.6 to 13.0 | <.001 |
| HSCT: Yes versus no | 2.1 | 1.2 to 3.7 | .006 |
Influence of Autologous HSCT on Survival in Subgroup Analyses
We performed subgroup analyses in an attempt to identify patients who would potentially benefit from HSCT. In those patients who were in CR1 or CR2 at the time of HSCT or surveillance after remission, disease-specific survival rates were significantly higher in the HSCT group compared with the control group (disease-specific 5-year survival rate, 87.3% for HSCT vs 67.8% for non-HSCT; P = .027, log-rank test) (Figure 2A). We also performed subgroup analyses according to NK-IPI risk group (low risk vs high risk) (Figure 2B, C). In the low-risk group (group 1-2), there was no significant difference in survival between the HSCT and control groups (disease-specific 5-year survival rate, 86.7% for HSCT [n = 16] vs 69.1% for non-HSCT [n = 38]; P = .291, log-rank test) (Figure 2B). In the high-risk group (group 3-4), however, the HSCT group (n = 6) seemed to have more favorable clinical course compared with the control group (n = 27) in terms of survival with marginal statistical significance (disease-specific 5-year survival rate, 100% vs 51.2%; P = .053, log-rank test) (Figure 2C). For those patients who were in PR at the time of HSCT or other treatment, there was no difference in survival between the HSCT group and the control group (disease-specific 5-year survival rate, 29.6% vs 22.2%; P = .472, log-rank test) (data not shown).
Figure 2
A) OS according to HSCT in CR patients, B) Impact of HSCT on survival of the low NKIPI group (CR), C) Impact of HSCT on survival of the high NKIPI group (non-CR).
Subgroup analyses on non-CR patients at the time of HSCT or non-HSCT treatment (chemotherapy with or without RT or RT alone) revealed no significant difference in disease-specific survival rates between the HSCT and control groups (1-year survival rate, 66.7% vs 28.6%; P = .141, log-rank test) (Figure 3A). Further subgroup analyses demonstrated no notable survival difference between the 2 groups in non-CR patients when subcategorized into low-risk and high-risk NK-IPI groups (Figures 3B and C).
Figure 3
A) OS according to HSCT in non-CR patients, B) Impact of HSCT on survival of the low NKIPI group (non-CR), C) Impact of HSCT on survival of the high NKIPI group (non-CR).
Discussion
This study represents the first multinational collaborative study exploring the role of HDC and HSCT in the treatment of patients with NK/T cell lymphomas. Although HSCT to treat other types of lymphomas (especially diffuse large B cell lymphoma) has been studied extensively, the definite role of and specific indications for HSCT in treating NK/T cell lymphomas have not yet been systematically established. We and few other groups have previously reported poor survival outcome in patients with NK/T cell lymphomas 3, 4, 5, 6. Although several studies have investigated the role of HSCT in treating NK/T cell lymphomas 13, 14, 15, 16, 17, they could not conclusively demonstrate the survival benefit from HSCT due to a small number of patients and the lack of a control arm. To overcome these obstacles, we undertook a multinational, multicenter matched control study to determine the potential survival benefit of HSCT in treating NK/T cell lymphomas, as well as to identify subgroups of patients who might benefit the most from HSCT.
Our data reveal several interesting findings. There was a trend toward better survival in the HSCT patients compared with the historical control group, although the difference was not statistically significant (disease-specific 5-year survival rate, 56.2% for HSCT vs 47.6% for non-HSCT; P = .127). The impact of HSCT on survival was significantly retained at multivariate level, with a 2.1-fold (95% CI = 1.2 to 3.7) reduced risk of death (P = .006). The most important prognostic factor influencing RFS and survival after HSCT was disease status at the time of transplantation (P < .001) (Table 2). Patients who did not attain CR at the time of transplantation had a 7.2-fold (95% CI = 4.4 to 11.6) greater risk of death compared with those who were in CR (data not shown).
Furthermore, disease-specific survival was significantly better in patients in CR in the HSCT group compared with those in the control group (disease-specific 5-year survival rate, 87.3% vs 67.8%; P = .027). The report of the International Consensus Conference on High-Dose Therapy with Hematopoietic Stem Cell Transplantation in Aggressive Non-Hodgkin's Lymphomas recommended front-line HSCT only in patients who achieve CR [21]. In particular, the patients with high NKIPI demonstrated notably improved survival after undergoing HSCT (Figure 2C), although the small number of cases in this subgroup limited the statistical power (P = .053). These patients need longer follow-up to allow any conclusions to be drawn on the statistical significance in survival difference. Based on our findings, we suggest that HSCT should be carefully considered for postremission consolidation therapy in patients with NK/T cell lymphomas, especially those with high NKIPI risk scores.
In contrast, subgroup analyses on non-CR patients at the time of HSCT or non-HSCT treatment found that disease-specific survival rates were not significantly prolonged in the HSCT group compared with the control group (1-year survival rate, 66.7% vs 28.6%; P = .141 [Figure 3A]. This finding is in agreement with previous studies that found negative outcomes of transplantation in a refractory disease state 20, 22, 23, 24. The segregation of patients based on NKIPI was not statistically significant in non-CR patients, although a trend toward better survival was seen in those patients with higher NKIPI who underwent autologous HSCT (P = .064; Figure 3C). Whether or not HSCT should be considered in patients with refractory NK/T cell lymphomas, especially those with high NKIPI scores, remains to be determined. Our findings do suggest that patients with refractory NK/T cell lymphomas should be offered therapy with investigational agents or reduced-intensity allogeneic HSCT in the context of clinical trials.
Although HDC/HSCT seemed to confer a survival advantage in our patients with NK/T cell lymphomas, especially those in the high-risk NKIPI group, only 66% of the patients receiving HDC/HSCT achieved CR, of whom 41.9% (n = 12) eventually experienced relapse. In addition, the role of HDC/HSCT was not definite in the patients with PR (disease-specific 5-year survival rate, 29.6% HSCT vs 22.2% for non-HSCT; P = .472). A possible explanation for the low CR rate and high relapse rate may be the inefficiency of the conditioning regimens used. Analyzing the efficacy of the conditioning regimen in this study is difficult because of the heterogeneity of the treatment protocols used. Nevertheless, most of the patients received a Cy-based conditioning regimen, which could be a target for a multidrug-resistance gene. Allogeneic HSCT possibly can have a graft-versus-lymphoma effect and reduce relapse rate at the expense of high TRM 25, 26. Another possible strategy to improve the treatment outcome of HDC/HSCT may be to perform transplantation before chemotherapy resistance is allowed to progress, such as when the patient is in CR1 [27]. Consequently, more multinational prospective studies incorporating novel therapies should be undertaken to improve survival in these patients.
Despite the adoption of a matched control design to minimize potential biases, our study is still limited by the retrospective nature of the analyses. To reduce bias, we matched 2 known prognostic factors known to influence survival in NK/T cell lymphomas: disease status at time of transplantation and NKIPI. Previous studies have confirmed the attainment of CR at the time of transplantation as one of the most powerful prognostic factors for survival after HSCT 15, 19, 20, 23, 28. Thus, we selected a 1:3 ratio of HSCT patients to control patients who did not undergo HSCT as postremission consolidation therapy, but had surveillance alone. For the patients who did not achieve CR at the time of HSCT, we attempted to select control patients who received conventional therapy from the database. There are potential selection biases in the historical control group. The patients in the control group did not undergo HSCT mainly due to different practice guidelines among the institutions in the 3 different nations and differences in patient age. Moreover, the proportion of patients with non-CR (PR/SD/PD) was higher in the HSCT group, likely reflecting current treatment practices. But the clinical variables, including performance status, LDH level, IPI, presence of B symptoms, anatomic category, NK-IPI, disease status, and primary treatment modalities, were well balanced between the 2 arms. There were greater proportions of patients under age 60 years, but the prognostic impact of this was not significant at the univariate level (Table 2), which coincides with results from the Japanese and Korean series 6, 14, 29. Another weakness of the present study lies in the heterogeneity of the treatment modalities and HSCT protocols owing to retrospective data collection from 3 different databases from different institutions and different nations.
In summary, collectively, our data indicate that HSCT seemed to confer a survival benefit in patients who attained CR as postremission consolidation therapy. These findings suggest that, in particular, patients with high NKIPI risk scores (group 3-4) at diagnosis who attain CR should receive full consideration for autologous HSCT.
Acknowledgments
Financial disclosure: This study was supported by Samsung Medical Center grant OTX1070211.
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J. Lee and W.Y. Au contributed equally as first authors.
The authors have no conflicts of interest to declare.
Financial disclosure: See Acknowledgments on page 1364.
PII: S1083-8791(08)00405-9
doi:10.1016/j.bbmt.2008.09.014
© 2008 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 14, Issue 12 , Pages 1356-1364, December 2008
