High-dose therapy with autologous hematopoietic stem cell transplantation (auto-SCT) for peripheral T-cell lymphomas (PTCLs) has been evaluated as a consolidation of the first remission and salvage therapy for relapse.1, 2, 3, 4, 5, 6, 7 However, no randomized trial comparing conventional chemotherapy followed by auto-SCT and conventional chemotherapy alone has been performed. Although data for allogeneic (allo-) SCT in selected patients with PTCLs have been reported to be promising,8, 9, 10, 11, 12, 13 no large-scale prospective study has been performed thus far. To clarify the roles of auto- and allo-SCT in the treatment of PTCLs, the Japan Study Group for Cell Therapy and Transplantation conducted a retrospective study of SCT for patients with PTCLs with central review of pathology. The study protocol was approved by the institutional review board at each center.
We collected the clinical data of 336 patients with PTCLs diagnosed at 52 Japanese and 8 Korean centers between September 1991 and December 2008, obtained the pathological samples of 307 patients, and conducted central review of pathology on the basis of the World Health Organization classification (Supplementary Figure S1).14 Patients with adult T-cell leukemia/lymphoma (ATLL) and natural killer (NK) cell tumors, aged less than 15 years at SCT and who received a planned tandem SCT were excluded. Following the review, we analyzed the data of 231 patients (135 auto-SCTs and 96 allo-SCTs).
Patient characteristics are summarized in Table 1. The clinical characteristics at SCT in the auto-SCT group were more favorable than those in the allo-SCT group except for median age (52 years in the auto-SCT group vs 45 years in the allo-SCT group). The proportion of patients previously treated with three or more chemotherapy regimens in the auto-SCT group was lower than that in the allo-SCT group (20% vs 60%, P<0.0001). The proportion of patients with stage III or IV disease at SCT in the auto-SCT group was lower than that in the allo-SCT group (29% vs 70%, P<0.0001). The transplantation procedures are summarized in Supplementary Table S1.
The median follow-up period for surviving patients was 46 months (range, 2.3–136 months). The 5-year overall survival (OS) and progression-free survival rates after allo-SCT for PTCLs were comparable to those after auto-SCT (48% vs 46%, P=0.34, Figure 1a; 40% vs 37%, P=0.54, Figure 1b) even though the allo-SCT group had more unfavorable factors than the auto-SCT group. The 5-year non-relapse mortality and relapse/disease progression (PD) rates in the allo- and auto-SCT groups were 33% and 15% (P=0.0003, Figure 1c) and 40% and 57% (P=0.12, Figure 1d), respectively. According to the disease status at SCT, the 5-year OS rates in the allo-SCT group were 69% in first complete remission or partial remission (CR1/PR1, n=16), 28% in second CR or PR (CR2/PR2, n=16), 43% in the resistant relapse (n=25) and 45% in primary refractory disease (n=20) (P=0.41, Figure 1e). The 5-year OS rates in the auto-SCT group were 62% in CR1/PR1 (n=72), 36% in CR2/PR2 (n=33) and 10% in primary refractory disease (n=10) (P<0.0001, Figure 1f). In patients with non-CR1/PR1 at SCT, the 5-year relapse/PD rate in the allo-SCT group was significantly lower than that in the auto-SCT group (44% vs 74%, P=0.003, Figure 1g), which may have contributed to the longer OS in patients who received allo-SCT. According to the three main histologic subtypes, the 5-year OS rates in the allo-SCT group were 41% in PTCL-not otherwise specified (NOS, n=48), 55% in angioimmunoblastic T-cell lymphoma (AITL, n=20) and 38% in anaplastic large cell lymphoma (ALCL, n=8) (P=0.24, Supplementary Figure S2a). The 5-year OS rates in the auto-SCT group were 32% in PTCL-NOS (n=55), 61% in AITL (n=47) and 55% in ALCL (n=20) (P=0.35; Supplementary Figure S2b). Reduced-intensity conditioning (RIC) allo-SCTs (n=62, median age: 55 years (range, 18–69 years)) showed little improvement in the 5-year OS compared with myeloablative allo-SCTs (n=34, median age: 39 years (18–57 years)) (51% vs 46%, P=0.85; Supplementary Figure S2c). The 5-year OS rates of allo-SCT patients who had received (n=25) and who had not received prior autograft (n=71) were not significantly different (40% vs 52%, P=0.98; Supplementary Figure S2d).
In the allo-SCT group with 96 patients, grade II–IV and III–IV acute graft-vs-host disease (GVHD) occurred in 40 (42%) and 15 patients (16%), respectively. Chronic GVHD occurred in 36 (50%) of the 72 evaluable patients, with the extensive type in 21 patients (29). Secondary malignancy occurred in 2 (2%) and 9 (7%) patients in the allo- and auto-SCT groups, respectively (Supplementary Table S2). Of the 44 and 74 patients who died after allo- and auto-SCT, 11 (25%) and 14 (19%) patients, respectively, died of infection, which was the major cause of non-relapse-related death (Supplementary Table S3).
The adverse prognostic factors for OS in the allo-SCT group were old age at SCT (>50 years, hazard ratio (HR): 1.81, 95% confidence interval (CI): 1.23–2.67, P=0.003), poor performance status (PS) at SCT (>1, HR: 2.12, 95% CI: 1.34–3.34, P=0.001) and cord blood use (HR: 2.93, 95% CI: 1.48–5.81, P=0.002); the adverse prognostic factors for OS in the auto-SCT group were PS at SCT (>2, HR: 2.66, 95% CI: 1.49–4.74, P=0.001) and disease status at SCT (non-CR1/PR1, HR: 2.47, 95% CI: 1.52–4.00, P<0.001) (Supplementary Table S4).
Approximately 40% of the patients who received allo-SCT in refractory status exhibited prolonged OS. Although two-thirds of the patients received RIC before allo-SCT, the results of auto- and allo-SCT were comparable, suggesting a graft-versus-PTCL effect. Previous reports on the relapse/PD rate of PTCL patients who received allo-SCT in refractory status are limited. An Italian group reported a higher relapse/PD rate in allo-SCT for PTCLs with refractory disease than our study (77% vs 44% at 5 years).11 Conversely, two previous reports of allo-SCT in PTCLs with a high percentage of refractory/relapsed disease (63% and 51%) exhibited low relapse/PD rates (30% at 2 years from the City of Hope12 and 20% at 3 years from the European Group for Blood and Marrow Transplantation13). Thus, the difference in the relapse/PD rates of PTCL patients who received allo-SCT indicates the limitations of retrospective studies, including different percentages of patients in non-remission status and selection bias. The efficacy of allo-SCT for PTCLs needs to be prospectively assessed according to the disease status (that is, CR1/PR1, CR2/PR2, and refractory status). Further, randomized trials (that is, chemotherapy vs chemotherapy followed by allo-SCT; auto-SCT vs allo-SCT) should be conducted in each disease status.
The OS rate of auto-SCT for PTCL patients in CR1/PR1 (62% at 5 years, n=72) in our study was similar to that in other retrospective studies, that is, 62% at 2 years (CR1, n=31)1 and 60% at 3 years (n=28),2 and that in a Nordic prospective phase II study on up-front auto-SCT (61% at 5 years for the cohort receiving SCT, n=115).7 Further, our study also demonstrated that CR1/PR1 at auto-SCT was a factor that favorably affected outcomes. Although the auto-SCT group in our study exhibited results comparable to those of previous reports, the survival curve of the CR1/PR1 patients did not plateau. Therefore, it is still difficult to conclude that the up-front auto-SCT strategy significantly improves OS for previously untreated PTCLs without randomized trials comparing up-front auto-SCT and conventional chemotherapy.
Our study included a central review of pathology. The diagnosis of PTCL was confirmed in 231 of the 307 patients with adequate samples (75%). Additionally, the International T-cell Lymphoma Project reported that a significant proportion of patients with PTCL had different pathological diagnoses; in this study, the original diagnosis was confirmed in 1 153 (88%) of the 1 320 patients.15 Although the agreement of the experts with the consensus diagnosis was good (>90%) for anaplastic lymphoma kinase (ALK)-positive ALCL, ATLL and NK/T-cell lymphoma, mainly because of the presence of specific diagnostic markers, it was generally poor (<85%) for the other lymphoma subtypes.15 As the patients with ATLL and NK-cell tumors were excluded before the implementation of the central review of pathology, it is only natural that the agreement of the experts with the consensus diagnosis was slightly poorer than that reported in the International T-cell Lymphoma Project. Although the different patient characteristics in the auto- and allo-SCT groups and the retrospective comparison of both groups are potential limitations of our study, the implementation of the central review of pathology enhances the quality of our study. Thus, central reviews should ideally be included in future clinical studies for PTCLs.
In conclusion, despite unfavorable clinical features at transplant in the allo-SCT group, the survival of this group was comparable to that of the auto-SCT group. Therapeutic strategies including allo-SCT for PTCLs are promising and should be evaluated in future prospective studies.
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We would like to thank pathologists Dr Hironori Haga and Dr Yoon Kyung Jeon for attending the consensus conference. We also thank the JSCT Office for outstanding data management. Further, we thank Dr Yoichi Takaue, Dr Kensei Tobinai, Dr Takashi Watanabe and Dr Shigeo Fuji for the discussions. This work was supported by a grant from the Regional Medicine Research Foundation (Utsunomiya, Japan).
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Leukemia website
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Kim, S., Yoon, S., Suzuki, R. et al. Comparison of outcomes between autologous and allogeneic hematopoietic stem cell transplantation for peripheral T-cell lymphomas with central review of pathology. Leukemia 27, 1394–1397 (2013) doi:10.1038/leu.2012.321
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