1 Hospital Son Dureta, Palma de Mallorca; 2 Hospital Clinico Universitario, Salamanca; 3 Hospital Nuestra Señora de Aranzazu, San Sebastian; 4 Hospital 12 de Octubre, Madrid; 5 Hospital de la Santa Creu i Sant Pau, Barcelona; 6 Hospital Clinic i Provincial, Barcelona; 7 Hospital General de Jerez, Jerez de la Frontera; 8 Hospital de la Princesa, Madrid; 9 Institut Catala dOncologia, Barcelona; 10 Hospital de la Vall de Hebron, Barcelona; 11 Hospital Ramon y Cajal, Madrid; 12 Clinica Universitaria de Navarra, Pamplona; 13 Hospital Juan Canalejo, La Coruña; 14 Hospital Marques de Valdecilla, Santander, Spain
Received 7 July 2003; accepted 11 August 2003
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Abstract |
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T-cell immunophenotype constitutes an unfavorable prognostic factor in aggressive non-Hodgkins lymphomas. High-dose chemotherapy with autologous stem-cell rescue (HDC/ASCT) is the best salvage therapy for patients with aggressive B-cell lymphomas. However, results with this therapy in peripheral T-cell lymphoma (PTCL) are not well defined.
Patients and methods:
From January 1990 to December 1999, 115 patients with PTCL underwent HDC/ASCT inside the Grupo Español de Linfomas/Trasplante Autólogo de Médula Ósea (GEL-TAMO) registry. At diagnosis the median age was 41 years and 60% of patients presented with two or three risk factors from the adjusted International Prognostic Index (a-IPI). Thirty-two per cent of patients were transplanted in first complete response (CR), 62% in chemosensitive disease and 5% in refractory disease.
Results:
Eighty-six per cent of the patients attained a CR and 5% a partial response (PR). With a median follow-up of 37 months (range 1133), overall survival (OS), time-to-treatment failure (TTF) and disease-free survival (DFS) at 5 years was 56%, 51% and 60%, respectively; for the 37 patients transplanted in first CR, OS and DFS at 5 years were 80% and 79%, respectively. Lactase dehydrogenase (LDH), a-IPI and disease status pre-transplant were associated with outcome.
Conclusions:
More than half of patients with chemosensitive disease who were transplanted are expected to be alive at 5 years. We confirm the utility of the pre-transplant IPI system in predicting outcome. Salvage treatment results with HDC/ASCT in PTCL are similar to those found in corresponding aggressive B-cell lymphomas.
Key words: autologous transplantation, GEL-TAMO, peripheral T-cell lymphoma
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Introduction |
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After promising phase II studies [10], the randomized Parma study [11] established convincingly that high-dose chemotherapy with autologous stem-cell rescue (HDC/ASCT) is the best salvage therapy for patients with chemosensitive disease in the intermediate grade group of the Working Formulation of non-Hodgkin lymphomas (NHL). However, there are no data to determine whether PTCL behave differently from B-cell lymphomas in the salvage setting. Recent data in patients with chemosensitive disease suggest similar results with transplantation in PTCL, compared with the corresponding aggressive B-cell lymphomas [1215]. Furthermore, no data are available in patients with PTCL treated with HDC/ASCT in the frontline setting. In order to provide information regarding these issues, we report herein our experience in a cooperative group with 115 patients with PTCL classified according to the Revised EuropeanAmerican Lymphoma (REAL) classification who underwent HDC/ASCT. Our results suggest that the outcome of PTCL patients treated with HDC/ASCT does not differ from the published data on patients with B-cell aggressive NHL.
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Patients and methods |
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Histological diagnosis was established by the local pathologist in each center. Those cases who presented with difficult diagnostic features were sent for consultation to expert hematopathologists following recommendations of the group. Histological subtypes were as follows: 62.6%, PTCL unspecified; 21.8%, anaplastic large T-cell lymphoma; 7%, lymphoepiteloid T-cell lymphoma; 5.2%, angioimmunoblastic T-cell lymphoma; 2.6%, hepatosplenic /
T-cell lymphoma and 0.9% intestinal T-cell lymphoma. The disease stage was evaluated according to the Ann Arbor staging system and patients were staged according to standard procedures with a physical examination, blood and serum assays, chest X-rays and computed tomography of the neck, chest, abdomen and pelvis. Bone marrow aspirates and biopsies were obtained prior to high-dose chemotherapy as well as other staging procedures performed at diagnosis to test pre-transplant condition. Standard variables of the adjusted International Prognostic Index (a-IPI) [8] and other variables of known prognostic importance in these type of lymphomas were evaluated [16]. Tables 1 and 2 list the clinical characteristics of patients at diagnosis and at the moment of transplantation.
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Statistical methods
Overall survival (OS), time-to-treatment failure (TTF) and disease-free survival (DFS) were measured from the date of transplantation and were estimated according to the KaplanMeier method [18]. Comparisons among those variables of interest were performed by the log-rank test [19]. Multivariate analysis with those variables significant in univariate analysis was performed according to the Cox proportional hazard regression model [20]. However, ß2-microglobulin was excluded from multivariate analysis as it was only available in half of the patients. All P values reported were two-sided and statistical significance was defined as values of P <0.05.
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Results |
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Results of patients with T-cell ALCL versus other histologies
We analyzed patients with anaplastic large cell lymphoma (Rodriguez J et al., unpublished data) and compared them with the rest of the patients with other T-cell histological types. Interestingly we could not find any differences in the number of CRs, TTF, DFS and OS. We did not have any data available on anaplastic lymphoma kinase (ALK) expression in patients with ALCL [21, 22]. The same lack of a significant difference in outcome was observed in patients treated with transplant in first CR or first PR in both the anaplastic and non-anaplastic PTCL groups (data not shown).
Outcome of patients who received HDC/ASCT in the salvage setting
Seventy-eight patients were transplanted in first or subsequent PR (n = 44), second or more CR (n = 28) or RD (n = 6). Clinical characteristics at diagnosis and transplantation are shown in Tables 1 and 2. In this salvage setting actuarial OS, TTF and DFS at 5 years were 45% (95% CI 31% to 59%), 39% (95% CI 27% to 51%) and 49% (95% CI 34% to 64%), respectively. Interestingly, in this group, patients in first or subsequent PR pre-transplant had an evolution quite similar to patients in CR pre-transplant after salvage treatment. Indeed, there were no statistically significant differences between the 41 patients transplanted in PR and the 28 patients transplanted in second or subsequent CR as consolidation. OS, TTF and DFS at 5 years were 46% (95% CI 27% to 65%) versus 54% (95% CI 31% to 77%) (P = 0.808); 44% (95% CI 28% to 60%) versus 42% (95% CI 21% to 63%) (P = 0.706) and 62% (95% CI 42% to 82%) versus 42% (95% CI 21% to 63%) (P = 0.102) for the PR and CR groups, respectively, in the salvage setting. Finally, OS and TTF at 5 years for patients transplanted in RD were both 0%, indicating that HDC/ASCT is not an effective approach in this group of patients.
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Discussion |
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There is a paucity of data related to HDC/ASCT in the salvage or frontline setting in PTCL compared to B-cell lymphomas. However, a recent report from the M.D. Anderson Cancer Center [12] indicates a 36% OS and a 32% TTF at 3 years in a retrospective analysis of 36 heavily pretreated patients. Our findings confirm these results, as our 45% OS and 39% TTF in 78 patients transplanted in the salvage setting are at least as favorable as the corresponding results obtained with B-cell lymphoma in our experience, as well as that of other groups [12, 14, 23]. Indeed, the OS and TTF of a complete cohort of 452 patients of diffuse large-cell lymphoma who underwent HDC/ASCT were 53% and 43%, respectively [14]. Vose et al. [24] in a smaller study reported an even higher CR rate of 59% in 17 patients with PTCL who received HDC/ASCT as salvage therapy than the corresponding 24 patients with B-cell immunophenotype who achieved a CR of 42%; both groups had identical survival rates. Thus, we believe that the unfavorable prognosis associated with the T-cell immunophenotype, observed with frontline standard therapy, can be overcome with HDC/ASCT in the salvage setting.
Prognostic systems have proven their ability to differentiate distinct risk groups [8, 16]. Similar to the M.D. Anderson experience, our data confirm the validity of pre-transplant a-IPI and LDH to predict TTF and OS in these types of lymphomas. Interestingly, the tumor score reported by the M.D. Anderson group [16] was also associated with outcome. This system takes into consideration only variables related to the tumor and which incorporates ß2-microglobulin and bulky disease as risk factors. This system has been recently confirmed as an important predictor of outcome in PTCL [25]. However, the significance of the tumor score in univariate analysis was not confirmed in multivariate analysis, probably due to the relatively small number of patients with data (n = 52) and the small number of patients in the high-risk group of the tumor score at transplant (n = 6). Anyway, this score may be an important prognostic factor for patients transplanted with active disease, as actuarial survival at 3 years of patients transplanted in this high-risk group was 0%.
The other important prognostic factor for TTF was disease status at transplantation. The results in those patients transplanted in first CR are encouraging. Indeed, these patients have an estimated 5-years OS of 80% with a TTF and DFS of 79%. These data suggest that frontline HDC/ASCT in PTCL leads to a more favorable outcome. As most of these patients presented with un-favorable prognostic factors of a-IPI and/or tumor score, we believe that these data suggest that the dismal prognosis of T-cell immunophenotype and prognostic score systems may be overcome with frontline HDC/ASCT. However, only appropriate randomized studies can confirm this hypothesisyet, to the best of our knowledge, no formal randomized study, or specific data from randomized studies of aggressive NHL focusing on T-cell lymphoma, has so far been reported. In preliminary observations in an ongoing randomized study in the M.D. Anderson Center, comparing conventional chemotherapy versus chemotherapy followed by HDC/ASCT in poor-risk patients with aggressive lymphoma, 10 of 17 patients with PTCL randomized to the transplant group had a superior survival compared with the seven patients who received conventional chemotherapy [26]. In contrast, Mounier et al. [26] reached the opposite conclusion based on the lack of difference in the outcome of 16 patients with PTCL transplanted as part of the consolidation arm versus the 27 patients with PTCL randomized to sequential chemotherapy. Again, this controversy can only be resolved with an appropriately powered randomized study. At the same time, we need to be cautious since the population of patients consolidated in first CR is a select group with a median age of 31 years versus 42 years for the whole population.
Another important issue is the fact that eight of our 37 patients transplanted in first CR had anaplastic large-cell lymphoma (ALCL), which according to most reports, have a better prognosis than other T-cell lymphomas [27]. Indeed, Gisselbrecht et al. [9] reported a more favorable prognosis in patients with T-cell ALCL treated with different conventional chemotherapy regimens than the other subtypes of PTCL. However, analyzing the results in patients with anaplastic histology versus those with other histologies, we could not find any difference in outcome (OS, TTF and DFS) or distribution of prognostic factors, either in those transplanted in first CR or in the relapse setting. This suggests that with this therapeutic modality, there are no differences between T-cell ALCL and the rest of the PTCLs. Unfortunately, we could not gather information regarding the expression of ALK in these ALCLs, which could have established more reliable information regarding the prognosis of these patients [22, 28]. Indeed, ALK-positive ALCL may represent a distinct clinical disease with better prognosis than the corresponding ALK-negative cases.
In the salvage setting, another important issue is that patients in PR at the moment of transplantation, who are deemed CR post-transplant, did not have a different outcome compared with patients in second or subsequent CR consolidated with transplant. This may imply that achieving a PR with the salvage therapy prior to transplant would be enough to obtain comparable results provided they achieve a CR post-transplant. However, OS, TTF and DFS for refractory patients at transplant were 0%. Thus they do not benefit from this therapeutic modality and therefore other experimental strategies should be tested to improve their outcome.
In conclusion, our data show that more than half of the patients with PTCL transplanted with chemosensitive disease are expected to be alive at 5 years, confirming that there is no difference with respect to the larger group of B-cell lymphomas when patients are treated with this modality. Encouraging results were observed in patients transplanted in first CR, where 80% of patients are expected to be alive at 5 years. In addition, we can confirm the utility of the pre-transplant IPI system in predicting outcome. Finally, we suggest that the poor prognostic implication of the T-cell immunophenotype can be overcome with this therapeutic modality either in the salvage setting or as frontline therapy.
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Acknowledgements |
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Footnotes |
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