High-dose chemotherapy and autologous stem cell transplantation in peripheral T-cell lymphoma: the GEL-TAMO experience

J. Rodríguez1,+, M. D. Caballero2, A. Gutiérrez1, J. Marín3, J. J. Lahuerta4, A. Sureda5, E. Carreras6, A. León7, R. Arranz8, A. Fernández de Sevilla9, J. Zuazu10, J. García-Laraña11, J. Rifon12, R. Varela13, M. Gandarillas14, J. SanMiguel2 and E. Conde14

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 d’Oncologia, 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


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

T-cell immunophenotype constitutes an unfavorable prognostic factor in aggressive non-Hodgkin’s 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 1–133), 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


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Peripheral T-cell lymphoma (PTCL) constitutes the largest T-cell non-Hodgkin’s lymphoma group in adult patients [1]. Excluding cutaneous, lymphoblastic and human T-cell lymphoma virus- 1-associated T-cell leukemia/lymphoma, PTCL accounts for 10–15% of aggressive lymphomas [2]. However, different entities with different biology and probably distinct prognoses are included in this large group. Unfortunately, due to their relative rarity, few series with meaningful numbers of patients have been reported. The prognostic significance of the T-cell immunophenotype is a matter of controversy. Indeed, most [35] but not all series [6, 7] confer an unfavorable prognosis to the T-cell immunophenotype. Although the poor prognosis of PTCL has been explained by the higher unfavorable prognostic factor distribution [8], the T-cell phenotype constitutes an independent and significant unfavorable prognostic factor in most large series [5, 9].

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 European–American 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.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
From 1990 to 1999, 115 patients with a diagnosis of PTCL, according to the REAL classification [2], were included in the Grupo Español de Linfomas/Trasplante Autólogo de Médula Ósea (GEL-TAMO) registry. Patients were eligible to receive HDC/ASCT according to the following criteria: diagnosis of PTCL—excluding lymphoblastic or cutaneous lymphoma—who relapsed or failed to achieve complete remission after induction treatment. In addition, patients in first remission who were considered to have a high risk of relapse according to established adverse prognostic factors were included by the investigators in this registry and are analyzed as well. Patients with severe concomitant medical or psychiatric illnesses, central nervous system (CNS) involvement or human immunodeficiency virus (HIV) seropositivity were not eligible. Other criteria for ineligibility included a bilirubin level >1.5 mg/dl, cardiac ejection fraction <50% and a pulmonary function test and diffusing lung capacity of <50% of predictive value.

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 {gamma}/{delta} 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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Table 1. Clinical characteristics at diagnosis
 

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Table 2. Clinical characteristics at transplant
 
Treatment plan
Pre-transplant regimens were not uniform, but were based mostly on anthracycline-based regimens (Table 1). Preparative regimens and other transplant-related factors are depicted in Table 3. Fifty (43%) patients received the carmustine, etoposide, cytarabine and melphalan (BEAM) regimen; 37 patients (32%) bleomycin, etoposide, doxorubicin and cyclophosphamide (BEAC); 14 (12%) cyclophosphamide/total body irradiation (TBI) and 14 (12%) other regimens. Eighty (70%) patients received mobilized peripheral blood (PB) as stem cell product and 35 patients (30%) bone marrow. Of the 80 cases that received PB stem cells, 33 (41%) were mobilized with granulocyte colony-stimulating factor (G-CSF), 42 (52%) with G-CSF and chemotherapy, and five cases with chemotherapy alone.


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Table 3. Transplant-related factors
 
Response and follow-up criteria
Response to therapy was evaluated 1, 3 and 6 months post-transplant and every 6 months thereafter by the investigator responsible in each center. Evaluations followed the standard guidelines [17] with physical examination, complete blood counts, serum chemistry panel, bone marrow aspiration and biopsy and radiological studies as aforementioned. Complete response (CR) was defined as the disappearance of all clinical evidence of lymphoma for a minimum of 4 weeks with no persisting symptoms related to the disease. Prior to transplantation complete restaging was available in all patients. To categorize a patient as a complete responder after HDC/ASCT, residual masses had to be unchanged for >=6 months. Partial response (PR) was defined as a >50% decrease in the sum of the products of the two longest diameters of all measurable lesions for at least 4 weeks and non-measurable lesions had to decrease by >=50%. No lesions could increase in size and no new lesion could appear. Progressive disease (PD) was defined as any increase >25% in the sum of the diameter of any measurable lesions or the appearance of a new lesion. Transplant-related mortality was defined as death within 100 days after high-dose therapy not related to the disease, relapse or progression. Toxic mortality was considered at any time if it was related to the procedure.

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 Kaplan–Meier 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.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Outcome
Response to transplantation was as follows: 98 of 114 (86%) patients suitable for response assessment achieved a CR, six (5%) PR, three (3%) stable disease and seven (6%) PD. At a median follow-up of 37 months (1–133), 73 (63%) patients are alive with an estimated OS at 5 years of 56% (95% CI 45% to 67%) and a TTF at 5 years of 51% (95% CI 41% to 61%) (Figures 1 and 2). The DFS at 5 years was 60% (95% CI 49% to 71%) for complete responders. After a median follow-up time after transplantation of 37 months (range 1–133) 42 patients have died. Causes of death were PD in 32 (76%) patients and nine of 115 patients (8%) died of transplant-related complications. One patient died of myelodysplastic syndrome.



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Figure 1. Overall survival.

 


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Figure 2. Time-to-treatment failure and disease-free survival.

 
Analysis of pre-transplant prognostic factors for OS
Thirty-seven patients were transplanted in first CR. The OS at 5 years for this group of patients was 80% (95% CI 65% to 95%). Clinical characteristics of these patients are listed in Tables 1 and 2. Twenty-eight patients were in second or more CR pre-transplant. These patients had an OS at 5 years of 50% (95% CI 37% to 63%). Forty-four patients were in PR pre-transplant, of these 70% reached a CR after transplantation and 49% (95% CI 41% to 57%) were alive at 5 years. None of the six patients with refractory disease (RD) pre-transplant survived after the transplant. Analyzed by group, there was statistically significant longer survival in patients transplanted in first CR compared with those transplanted in second or more CR or PR (P = 0.007) as well as for patients in CR compared with PR and RD (P = 0.002). As highlighted in Table 4 using univariate analysis, the following factors were associated with longer survival: age <41 years (median age of the population), transplantation in first CR or chemosensitive disease, an ECOG performance status of 0 or 1, no extranodal disease, normal LDH, ß2-microglobulin <3 µg/dl, zero or one risk factors of the a-IPI and two or less risk factors of tumor score [16]. However, using multivariate analysis only LDH predicted survival [hazard ratio 0.16 (95% CI 0.07–0.36); P <0.001] (Figure 1).


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Table 4. Univariate analysis of risk factors at transplantation
 
Analysis of prognostic factors for TTF and DFS
Table 4 depicts the factors associated with TTF by univariate analysis. Briefly, age <41 years, an a-IPI of 0 or 1, a tumor score of 0–2, patients in first CR or CR, no extranodal disease, normal LDH and normal ß2-microglobulin were associated with a superior TTF. By multivariate analysis only transplant in first CR [hazard ratio 0.35 (95% CI 0.15–0.80); P = 0.014] or zero or one risk factors of a-IPI [hazard ratio 0.26 (95% CI 0.12–0.60); P = 0.002] were related to a better TTF (Figure 2). For DFS only was disease status at transplantation associated with outcome. Indeed, patients in first CR or patients in first PR who achieved a CR post-transplant had a significantly longer DFS at 5 years [79% (95% CI 65% to 93%) for first CR and 61% (95% CI 36% to 86%) for first PR] (P = 0.3) than patients in second or more CR pre-transplant [42% (95% CI 22% to 62%] (P = 0.02) (Figure 2).

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.


    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The prognostic significance of a T-cell immunophenotype has been addressed in several studies [37, 9, 12] with conflicting results. Indeed, although it is generally accepted that the T-cell immunophenotype confers an adverse prognosis independent of the IPI, not all studies agree with this statement [6, 7]. Nevertheless, Melnyk et al. [5] from the University of Texas M.D. Anderson Cancer Center (Houston, TX, USA) conducted a large retrospective study involving 560 patients who received standard treatment, and observed a more unfavorable distribution in patients with T-cell immunophenotype than in the corresponding B-cell lymphomas, with an OS of 38% at 5 years compared with 63% for the latter group. Interestingly this difference persisted when patients were stratified according to the IPI risk system, suggesting that the T-immunophenotype may be an independent unfavorable prognostic factor. Recently, Gisselbrecht et al. [9], in a large series of patients with aggressive diffuse large-cell non-Hodgkin’s lymphoma, confirmed that the T-cell phenotype is an independent unfavorable prognostic factor.

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 hypothesis—yet, 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.


    Acknowledgements
 
We thank Dr Fernando Cabanillas for his important contribution in the critical review of this work.


    Footnotes
 
+ Correspondence to: Dr J. Rodríguez, Servicio de Hematología, Hospital Son Dureta, Av/ Andrea Doria 55, Palma de Mallorca 07014, Spain. Tel: +34-971-175000; Fax: +34-971-175500; E-mail: jrodriguez{at}hsd.es Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. The Non-Hodgkin’s Lymphoma Classification Project. Blood 1997; 89: 3909–3918.[Abstract/Free Full Text]

2. Harris NL, Jaffe ES, Stein H et al. A revised European–American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84: 1361–1392.[Free Full Text]

3. Armitage JO, Vose JM, Linder J et al. Clinical significance of immunophenotype in diffuse aggressive non-Hodgkin’s lymphoma. J Clin Oncol 1989; 7: 1783–1790.[Abstract]

4. Coiffier B, Brousse N, Peuchmaur M et al. Peripheral T-cell lymphomas have a worse prognosis than B-cell lymphomas: a prospective study of 361 immunophenotyped patients treated with the LNH-84 regimen. Groupe d‘Etude des Lymphomes Agressives (GELA). Ann Oncol 1990; 1: 45–50.[ISI][Medline]

5. Melnyk A, Rodriguez A, Pugh WC, Cabannillas F. Evaluation of the Revised European–American Lymphoma classification confirms the clinical relevance of immunophenotype in 560 cases of aggressive non-Hodgkin’s lymphoma. Blood 1997; 89: 4514–4520.[Abstract/Free Full Text]

6. Cheng AL, Chen YC, Wang CH et al. Direct comparisons of peripheral T-cell lymphoma with diffuse B-cell lymphoma of comparable histological grades—should peripheral T-cell lymphoma be considered separately? J Clin Oncol 1989; 7: 725–731.[Abstract]

7. Kwak LW, Wilson M, Weiss LM et al. Similar outcome of treatment of B-cell and T-cell diffuse large-cell lymphomas: the Stanford experience. J Clin Oncol 1991; 9: 1426–1431.[Abstract]

8. A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 1993; 329: 987–994.[Abstract/Free Full Text]

9. Gisselbrecht C, Gaulard P, Lepage E et al. Prognostic significance of T-cell phenotype in aggressive non-Hodgkin’s lymphomas. Groupe d‘Etudes des Lymphomes de l’Adulte (GELA). Blood 1998; 92: 76–82.[Abstract/Free Full Text]

10. Philip T, Armitage JO, Spitzer G et al. High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin’s lymphoma. N Engl J Med 1987; 316: 1493–1498.[Abstract]

11. Philip T, Guglielmi C, Hagenbeek A et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 1995; 333: 1540–1545.[Abstract/Free Full Text]

12. Rodriguez J, Munsell M, Yazji S et al. Impact of high-dose chemotherapy on peripheral T-cell lymphomas. J Clin Oncol 2001; 19: 3766–3770.[Abstract/Free Full Text]

13. Kewalramani T, Nimer S, Zelenetz A et al. Similar outcomes for chemosensitive (CS) relapsed or primary refractory peripheral T-cell lymphoma (PTCL) and diffuse large B-cell lymphoma (DLBCL) treated with autologous transplantation (ASCT). Blood 2002; 100: 646a.

14. Caballero MD, Perez-Simon JA, Iriondo A et al. High-dose therapy in diffuse large cell lymphoma: results and prognostic factors in 452 patients from the GEL-TAMO Spanish Cooperative Group. Ann Oncol 2003; 14: 140–151.[Abstract/Free Full Text]

15. Blystad AK, Enblad G, Kvaloy S et al. High-dose therapy with autologous stem cell transplantation in patients with peripheral T cell lymphomas. Bone Marrow Transplant 2001; 27: 711–716.[CrossRef][ISI][Medline]

16. Rodriguez J, Cabanillas F, McLaughlin P et al. A proposal for a simple staging system for intermediate grade lymphoma and immunoblastic lymphoma based on the ‘tumor score’. Ann Oncol 1992; 3: 711–717.[Abstract]

17. Cheson BD, Horning SJ, Coiffier B et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol 1999; 17: 1244.[Abstract/Free Full Text]

18. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.[ISI]

19. Peto R, Pike MC, Armitage P et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples. Br J Cancer 1977; 35: 1–39.[ISI][Medline]

20. Cox DR. Regression models and life-tables. J R Stat Soc 1972; 34: 187.[ISI]

21. Shiota M, Nakamura S, Ichinohasama R et al. Anaplastic large cell lymphomas expressing the novel chimeric protein p80NPM/ALK: a distinct clinicopathologic entity. Blood 1995; 86: 1954–1960.[Abstract/Free Full Text]

22. Gascoyne RD, Aoun P, Wu D et al. Prognostic significance of anaplastic lymphoma kinase (ALK) protein expression in adults with anaplastic large cell lymphoma. Blood 1999; 93: 3913–3921.[Abstract/Free Full Text]

23. Song KW, Mollee P, Keating A, Crump M. Autologous stem cell transplant for relapsed and refractory peripheral T-cell lymphoma: variable outcome according to pathological subtype. Br J Haematol 2003; 120: 978–985.[ISI][Medline]

24. Vose JM, Armitage JO, Bierman PJ et al. Salvage therapy for relapsed or refractory non-Hodgkin’s lymphoma utilizing autologous bone marrow transplantation. Am J Med 1989; 87: 285–288.[ISI][Medline]

25. Lee HK, Wilder RB, Jones D et al. Outcomes using doxorubicin-based chemotherapy with or without radiotherapy for early-stage peripheral T-cell lymphomas. Leuk Lymphoma 2002; 43: 1769–1775.[CrossRef][ISI][Medline]

26. Mounier N, Simon D, Haioun C et al. Impact of high-dose chemotherapy on peripheral T-cell lymphomas. J Clin Oncol 2002; 20: 1426–1427.[Free Full Text]

27. Tilly H, Gaulard P, Lepage E et al. Primary anaplastic large-cell lymphoma in adults: clinical presentation, immunophenotype, and outcome. Blood 1997; 90: 3727–3734.[Abstract/Free Full Text]

28. Falini B, Pileri S, Zinzani PL et al. ALK+ lymphoma: clinico-pathological findings and outcome. Blood 1999; 93: 2697–2706.[Abstract/Free Full Text]