Peripheral T-cell lymphoma (PTCL) is generally characterized by poor prognosis after conventional chemotherapy compared with aggressive B-cell lymphoma. To elucidate the role of high-dose chemotherapy (HDCT) with auto-SCT, we retrospectively analyzed the outcomes of 39 patients with PTCL who received HDCT and auto-SCT between 1990 and 2005. Eleven patients were histologically typed as angioimmunoblastic, nine as anaplastic large-cell lymphoma, seven as natural killer/T-cell lymphoma and twelve as PTCL unspecified. Clinical conditions at transplantation were complete response (CR) in 27 patients and non-CR in 12 patients. Thirty-two patients received a pre-transplant conditioning regimen (MCEC) comprising ranimustine, carboplatin, etoposide and CY, and seven did other TBI-based regimens. Rapid engraftment was obtained in all cases, and transplant-related death was not seen. An estimated 5-year OS was 62.1% with a median follow-up of 78 months. The 5-year OS was significantly higher in patients transplanted during complete response than in those during other disease status (71.4% vs 27.3%, P=0.046). HDCT supported by auto-SCT may therefore be effective as consolidation in CR for PTCL treatment.
Peripheral T-cell lymphomas (PTCLs) are neoplasms derived from mature T cells and natural killer (NK) cells. They account for <10% of non-Hodgkin's lymphoma (NHL) cases. PTCLs are divided into several subtypes such as PTCL unspecified (PTCL-U), systemic anaplastic large-cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma and NK/T-cell lymphoma.1 PTCLs show distinct variations in different geographic regions and races; a higher proportion of NHL is seen in Asia.2
Novel and effective agents such as rituximab and yttrium-90 ibritumomab tiuxetan have benefited patients with aggressive B-cell NHL.3 Several studies have showed the superiority of high-dose chemotherapy (HDCT) with auto-SCT to conventional chemotherapy for patients with aggressive B-cell NHL as consolidation after the initial response.4, 5 Compared with aggressive B-cell NHL, the prognosis of PTCL patients is considerably poorer if they are treated with CY, doxorubicin, vincristine and prednisone (CHOP) or CHOP-like regimens.6, 7 Survival advantage of HDCT with auto-SCT for PTCL patients is contentious because most studies have involved small series and short-term follow-up.8, 9, 10
Since 1990, in Fukuoka Blood and Marrow Transplantation Group (FBMTG), HDCT with autologous PBSCT (auto-PBSCT) has been evaluated as consolidation for patients in CR1 or partial response (PR) 1, and as salvage for patients with relapsed and refractory disease, to improve PTCL outcomes. In this study, we retrospectively analyzed the results of 39 patients with PTCL who received HDCT with auto-PBSCT to clarify the efficacy of this treatment.
Patients and methods
Between January 1990 and June 2005, 39 patients who received HDCT with auto-PBSCT for PTCL were enrolled into this study at four institutions of FBMTG in Japan. Histology revealed that nine patients had ALCL, eleven had angioimmunoblastic T-cell lymphoma, seven had NK/T-cell lymphoma and twelve had PTCL-U. Clinical characteristics at diagnosis are shown in Table 1. Stage at diagnosis was defined according to the Ann Arbor staging system.11 The age-adjusted International Prognostic Index (aa-IPI) at diagnosis was retrospectively evaluated in 36 of 39 patients (92%).12
Exclusion criteria were involvement of the central nervous system, inadequate major organ functions, concomitant malignancy and active viral infection (for example, hepatitis B, hepatitis C, human immunodeficiency virus).
Patients received anthracycline-containing regimens, mainly CHOP regimens (CY, doxorubicin, vincristine and prednisone), as an induction therapy. In addition to chemotherapy, most patients with NK/T-cell lymphoma also received local radiotherapy. Autologous PBSCs were collected during hematological recovery after treatment with a high-dose etoposide (500 mg/sqm for 3 days) or intermediate-dose Ara-C (500 mg/sqm two times daily for 5 days) followed by s.c. injection of G-CSF as previously described.3 The target cell dose was >2 × 106 CD34+ cells/kg in a PBSC harvest. Harvested PBSCs were cryopreserved until use. The median number of infused CD34+ cells was 5.7 × 106 cells/kg (range, 2.4–26.1).
Patient characteristics at transplantation are shown in Table 1. The median age at transplantation was 49 years (range, 16–68 years), and the median time from diagnosis to auto-PBSCT was 7 months (range, 2–29 months). At transplantation, 22 patients were in CR1, 1 in PR1, 9 in chemotherapy-sensitive relapse and 7 in a chemotherapy-resistant state. Thirty-two patients were chemotherapy-sensitive, whereas seven patients were chemotherapy resistant.
The conditioning regimen prepared for auto-PBSCT was referred to as MCEC. It consisted of ranimustine 200 mg/m2 on days –8 and –3, carboplatin 300 mg/m2 from days –7 to –4, etoposide 500 mg/m2 from days –6 to –4 and CY 50 mg/kg on days –3 and –2 in 32 patients (82.1%) as previously described.3 Five patients were treated with TBI-containing conditioning regimens. On day 0, unpurged PBSCs were reinfused followed by administration of G-CSF. Engraftment was confirmed by granulocyte counts >0.5 × 109/l and plt counts >20 × 109/l on three consecutive occasions, or independence of plt transfusion.
OS was defined as days from transplantation to death of any cause. Progression-free survival (PFS) was defined as days from transplantation to disease progression or death of any cause. TRM included all causes of death other than disease progression within 100 days after transplantation. Survival was estimated using the Kaplan–Meier method. Comparisons among those variables of interest at the time of diagnosis were performed by the log-rank test. All P-values reported were two-sided and statistical significance was defined at a P-value <0.05.
This study was conducted in accordance with the ethical guidelines mandated by the Declaration of Helsinki.
Engraftment and treatment-related complications
Engraftment was rapid and documented in all patients. The median days to granulocyte count >0.5 × 109/l and a plt count >20 × 109/l were 9 (range, 8–11) and 11.5 (range, 7–17), respectively. TRM were not observed. Significant adverse events scored as more than grade 3 according to the National Cancer Institute Common Toxicity Criteria were not seen.
Survival and progression of the disease
With a median follow-up time of 78 months (range, 7–127 months) after auto-PBSCT, CR was achieved and maintained in 23 patients: 17 patients in CR1/PR1, 2 in sensitive relapse and 4 in the chemotherapy-resistant state before transplantation. The 5-year OS and PFS were 62.2% (95% confidence interval (CI), 46.4–77.9%) and 60.6% (95% CI, 45.0–76.2%), respectively (Figure 1a). Progressive disease (PD) was observed in 14 patients: five patients in CR1, three in sensitive relapse and six in the chemotherapy-resistant state before transplantation. Median time to PD was 149 days (range, 28–3815 days) and cumulative incidence of PD at 5 years was 33.8 %. Sixteen patients died. The primary cause of death was PD in 13 patients; the other three patients eventually died of secondary leukemia on day 521, heart failure on day 826 and pneumonia on day 2587, respectively. These three patients died in CR.
To investigate the effect of HDCT with auto-PBSCT in the treatment of PTCL, we compared the outcomes of 23 patients with PTCL, who were in CR/PR1 at transplantation, with those of 64 patients with diffuse large B-cell lymphoma, who were in CR, CR of undetermined significance and PR at transplantation from 1990 to 2005. Patient characteristics were well balanced and not statistically different between the two groups with regard to age, time to transplantation and conditioning regimen. There was no difference in outcomes between these two groups; 5-year OS and PFS were 72.9% vs 75.4% (P=0.82) and 73.1% vs 57.1% (P=0.42), respectively (Figure 2).
Data were evaluated using univariate analysis with the use prognostic factors such as histology, age, disease status at transplantation, stage, aa-IPI and lactate dehydrogenase at diagnosis. Patients having chemotherapy-sensitive disease at the time of transplantation showed significantly better 5-year OS and PFS than those having chemotherapy-resistant disease; OS was 67.2% vs 38.1% (P=0.014) and PFS 67.5% vs 28.6% (P=0.033). Patients in CR1/PR1 at transplantation showed significantly better 5-year OS and PFS than those with other status; OS was 72.9% vs 45.8% (P=0.033) and PFS 73.1% vs 42.2% (P=0.023) (Figure 1b). The low score of aa-IPI was also a significant factor influencing survival; OS of patients at low risk by aa-IPI (score 0 and 1) and at high risk by aa-IPI (score 2 and 3) were 83.9% vs 49.2% (P=0.035) and PFS 76.9% vs 50.2% (P=0.070) (Figure 1c). Lactate dehydrogenase (
We reviewed these univariate analyses by the multivariate method using four parameters: histology, aa-IPI at diagnosis, and age and disease status at transplantation. Despite no significant difference by univariate analysis, we also included histology (ALCL or non-ALCL) as a parameter because it was shown to be a favorable marker in a previous report.13 Two independent factors (age and disease status at transplantation) were found to significantly influence survival (Table 2).
Progress in PTCL therapy is slow partly because of the rarity of the disease, variation in incidence according to geographic location and absence of a common marker for therapy using monoclonal antibodies. Consensus regarding optimal treatment for PTCL is therefore lacking, and the prognosis of PTCL is reported to be inferior to that of aggressive B-cell lymphoma. Despite high and good initial response rates, most patients with PTCL fare poorly and develop progression early during or shortly after sequential conventional chemotherapy.14 The 5-year survival reported is <30% with CHOP regimen or more intensive regimens, such as those used in LNH programs and Hyper CVAD regimen.15, 16, 17 Recent studies have shown the superiority of HDCT with auto-SCT to conventional sequential chemotherapy and salvage chemotherapy for patients with aggressive NHL.4, 5, 18 These studies included in part T-cell lymphomas, and have given encouraging retrospective results of PTCL patients treated by HDCT with auto-SCT; estimated OS was reported to be ∼30–50%, which was similar to that of aggressive B-cell NHL despite fewer cases analyzed. Thus, these results indicate that HDCT with auto-SCT can benefit some patient populations of PTCL, and the parameters preferentially indicated for HDCT with auto-SCT should be clarified. To address this issue, we retrospectively analyzed our results of 39 consecutive patients with PTCL who underwent HDCT with auto-PBSCT in our institutions (FBMTG) since 1990.
In our study, 5-year OS and PFS in PTCL patients who were autografted in CR1/PR1 were 72.9 and 73.1%, respectively. These values were comparable with the corresponding results in patients with aggressive B-cell lymphoma who underwent HDCT with auto-PBSCT (Figure 2). Detailed analysis suggests that HDCT with auto-SCT may be effective for PTCL patients who have maintained CR1 or PR1 at transplantation, as well those who were chemotherapy sensitive after relapse. aa-IPI and histology type did not affect OS and PFS by multivariate analysis. Of the 39 patients in our study, 23 patients underwent auto-PBSCT in CR1/PR1, 9 patients were in chemotherapy-sensitive relapse and 7 cases in refractory phase. Approximately, 75% of patients in remission and half of those after chemotherapy-sensitive relapse had a durable response. Only two of seven patients transplanted with refractory disease showed a prolonged response. Our results are comparable with previous studies. For example, 5-year OS was reported to be 80% in patients transplanted in CR1 and 45% in other status by the GEL-TAMO group;19 5-year OS was reported to be 76 and 30% in patients with CR1/PR1 and refractory disease by Stanford group;14 and 5-year OS was 80% in CR1 by EBMT group.20 Therefore, these data strongly indicate that HDCT with auto-SCT can be one of the treatment choices for patients with PTCL as consolidation after achieving initial response, or as salvage after sensitive relapse. This treatment would be less favorable for chemotherapy-resistant patients, with no long-term survivors after HDCT with auto-SCT.19
Previous studies have stated the importance of the histological type of PTCL on auto-SCT outcome. Jagasia et al.21 reported improved survival in ALCL type because these studies included relatively more cases of ALK-positive ALCL, which generally confers good prognosis. Corradini et al.10 reported that up-front auto-SCT could induce a high rate of long-term CR only in patients with ALK-positive ALCL. Although number of patients were limited and information about ALK was not available in any of the patients in our study, there was no significant difference in 3-year OS between ALCL and the other subtypes of PTCL (66.7% vs 59.1%; P=0.12). Similarly, City of Hope22 and Stanford series14 also showed no difference in survival after HDCT with auto-SCT based on histological subtypes of PTCL, although these studies also did not afford a sufficient number of cases to stratify by type and disease status. A large Korean multicenter retrospective analysis including 139 patients also reported no survival difference depending on histological subtypes of PTCL.23 Discrepancies in survival data from the several groups mentioned above may in part be due to the heterogeneity of histological subtypes of PTCL. Therefore, larger retrospective and prospective studies are required to evaluate prognostic factors influencing survival in each histological subtype of PTCL.
According to our study and previous reports, the patients who seemed to benefit from HDCT were those in first remission or sensitive relapse at the time of transplantation.8, 10 However, some risk factors, such as prognostic index for PTCL (PIT), IPI and β2-microglobulin, identified some proportion of the patients in remission, who did not benefit from HDCT.8, 24 Therefore, allogeneic SCT as consolidation or salvage for the patients with higher prognostic factors at diagnosis in remission should be investigated. Furthermore, chemotherapies with novel agents that aimed at increasing the CR rate have potential to improve the outcomes of auto-SCT.25
In conclusion, our retrospective analyses suggest that HDCT with auto-PBSCT is feasible and safe for the treatment of PTCL. It is necessary to elucidate who could be benefited by this treatment modality depending on clinical features, prognostic markers and histological subtypes. HDCT with auto-SCT after improved initial or salvage chemotherapy must be explored for better outcomes. Prospective clinical trials, including a sufficiently large study population for statistical power, are necessary to define the role of HDCT for this rare disease.
Conflict of interest
The authors declare no conflict of interest.
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We thank the medical and nursing staff working at the Fukuoka Blood and Marrow Transplantation Group for providing information on the patients.
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Numata, A., Miyamoto, T., Ohno, Y. et al. Long-term outcomes of autologous PBSCT for peripheral T-cell lymphoma: retrospective analysis of the experience of the Fukuoka BMT group. Bone Marrow Transplant 45, 311–316 (2010) doi:10.1038/bmt.2009.165
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