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© 2001 American Society for Clinical Oncology Impact of High-Dose Chemotherapy on Peripheral T-Cell LymphomasByFrom the Departments of Blood and Marrow Transplantation, Lymphoma, and Biomathematics, University of Texas M.D. Anderson Cancer Center, Houston, TX. Address reprint requests to Issa F. Khouri, MD, Department of Blood and Marrow Transplantation, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 423, Houston, TX 77030; email: ikhouri{at}notes.mdacc.tmc.edu
PURPOSE: To evaluate the outcome of high-dose chemotherapy (HDCT) and autologous or allogeneic hematopoietic transplantation in patients with peripheral T-cell lymphoma (PTCL) who experienced disease recurrence after prior conventional chemotherapy. PATIENTS AND METHODS: We performed a retrospective analysis of 36 PTCL patients from the University of Texas M.D. Anderson Cancer Center treated between 1989 and 1998 with HDCT and autologous or allogeneic hematopoietic transplantation.
RESULTS: A total of 36 patients were studied (29 received autologous transplantation, and seven received allogeneic transplantation). The overall survival rate at 3 years was 36% (95% confidence interval [CI], 23% to 59%), and the progression-free survival (PFS) rate was 28% (95% CI, 16% to 49%). The pretransplant serum lactate dehydrogenase level was the most important prognostic factor for both survival and PFS rates (P < .001). A Pretransplant International Prognostic Index score of CONCLUSION: Our results are comparable to the published data on HDCT in B-cell non-Hodgkin’s lymphoma (NHL) patients despite the fact that patients with PTCL are known to have a worse outcome compared with B-cell NHL patients. Considering the dismal outcome of conventional chemotherapy in PTCL patients, these data suggest the hypothesis that the poor prognostic implication of T-cell phenotyping in NHL might be overcome by frontline HDCT and transplantation.
PERIPHERAL T-CELL lymphoma (PTCL) makes up the majority of T-cell non-Hodgkin’s lymphomas (NHLs) in adult patients. Excluding cutaneous, lymphoblastic, and human T-cell lymphoma virus-1–associated T-cell leukemia/lymphoma, approximately 10% of NHLs are PTCL.1 PTCLs represent a heterogeneous group of lymphomas classified in the Revised European-American Lymphoma classification as mature T-cell NHLs.2 With the exception of a few series,3,4 most studies show a poorer prognosis with the presence of a T-cell immunophenotype5-7 when compared with the corresponding B-cell lymphomas. An analysis from our institution7 found the T-cell phenotype to be an independent adverse risk factor for lymphoma in all of the risk groups of either the International Prognostic Index (IPI)8 or tumor score.9 There is a lack of data on the effect of salvage therapy on PTCL. The Parma study established autologous bone marrow transplantation as the treatment of choice for patients with intermediate-grade NHL with chemosensitive relapse,10 according to the Working Formulation. Patients in resistant relapse and those who had primary refractory lymphoma did not benefit from this procedure.11 It is not known whether these results apply to T-cell lymphoma. Recently, encouraging results were reported in 16 patients with primary systemic CD30+ anaplastic large-cell lymphoma who underwent autologous bone marrow transplantation.12 We performed a retrospective analysis of 36 patients with PTCL who received high-dose chemotherapy (HDCT) and hematopoietic transplantation at the University of Texas M.D. Anderson Cancer Center. Our results were similar to the published data on HDCT and transplantation in patients with B-cell NHL.
Patient Eligibility All PTCL patients undergoing HDCT and hematopoietic transplantation at the University of Texas M.D. Anderson Cancer Center between 1989 and 1998 were included in this report. Patients were eligible to receive transplantation and HDCT if they experienced disease recurrence after conventional chemotherapy, had relapsed, or had refractory lymphoma. Patients with lymphoblastic lymphoma or cutaneous lymphoma were excluded. Patients with severe concomitant medical or psychiatric illnesses with active CNS involvement or who were seropositive for human immunodeficiency virus or human T-cell lymphoma virus-1 were ineligible. Other criteria for ineligibility included a bilirubin level greater than 2 mg/dL, a creatinine level greater than 1.5 mg/dL, a cardiac ejection fraction of less than 50%, and a pulmonary function test and diffusing lung capacity less than 50% of predicted value. A T immunphenotype was confirmed in all cases. The disease stage was evaluated according to the Ann Arbor staging system. Patients were staged according to standard procedures with a physical examination, serum chemistry assays, chest X-rays, and computed tomography of the neck, chest, abdomen, and pelvis. Bone marrow aspirates and biopsy specimens were obtained before HDCT.
Treatment Plan
Twenty-nine patients underwent autotransplantation. The stem-cell source in these patients was marrow13 or peripheral blood.16 Blood stem cells were mobilized with cytokines. Seven patients underwent allotransplantation (five received from HLA-identical, and two received from one antigen-mismatched sibling). Graft-versus-host disease prophylaxis consisted of cyclosporine/methotrexate (two patients), tacrolimus/methotrexate (two patients), cyclosporine/prednisone (two patients), and tacrolimus/prednisone (one patient). Patients received supportive care according to existing University of Texas M.D. Anderson Cancer Center protocols at the time of the transplants.
Response Criteria
Statistical Methods
Patient Characteristics and Outcome Patient characteristics at the time of transplantation are listed in Table 2. The median age was 43 years (range, 26 to 65 years). The median number of prior chemoregimens received was three (range, one to four). Both autologous and allogeneic patients had comparable pretransplant characteristics.
As of March 2001, 13 patients (36%) were alive with no evidence of disease (Table 3). The median follow-up time after transplantation was 43 months (range, 13 to 126 months).
OS and progression-free survival (PFS) rates at 3 years were 36% (95% confidence interval [CI], 23% to 59%) and 28% (95% CI, 16% to 49%), respectively. The 3-year probabilities of survival for the autologous and allogeneic groups were 39% (95% CI, 23% to 65%) and 29% (95% CI, 9% to 92%; P = .314), respectively (Fig 1). The PFS rates for the autologous and allogeneic groups were 32% (95% CI, 18% to 56%) and 14% (95% CI, 2% to 88%; P = .369), respectively.
Prognostic Factors Univariate analysis showed that the pretransplant serum lactate dehydrogenase level (Fig 2) was the most important prognostic feature that correlated with both survival and PFS (P < .001). Also, patients with an IPI score of 0 to 1 had better survival (Fig 3) but not PFS than patients with higher IPI scores. Patients with Ki-1 histology had a tendency to have better outcomes than other patients (four of these seven patients were alive and in remission). However, the difference is not statistically significant. Other factors that were not found to be significant included sex, disease stage, chemosensitivity, number of prior relapses, prior chemoregimen, marrow involvement, remission at transplant, and the source of stem cells.
Toxicity Twenty-three patients died (Table 3). The causes of death were progressive disease (15 patients), infection (four), graft-versus-host disease (two), cardiac failure (one), and secondary myelodysplasia (one). Six of these patients died in CR.
It is generally accepted that a T-cell immunophenotype constitutes an independent adverse prognostic factor in aggressive NHLs.5-7 Melnyk et al7 performed a large retrospective study involving 560 NHL–immunophenotyped patients who were treated with conventional chemotherapy at the University of Texas M.D. Anderson Cancer Center. When compared with patients with B-cell NHL, PTCL patients were overwhelmingly more likely to present with advanced stage III or IV disease and to have B symptoms. They were also more likely to have an elevated serum lactate dehydrogenase or B2 microglobulin level. In addition, with conventional chemotherapy, the 5-year probability of OS for these patients was 38% (95% CI, 35% to 54%) compared with 63% (95% CI, 53% to 73%; P = .001) for patients with B-cell lymphomas. This difference maintained its significance when results were stratified for the IPI and the University of Texas M.D. Anderson tumor score. Cumulative experience has shown that HDCT with stem-cell rescue is the most effective salvage therapy10 for patients with B-cell aggressive lymphoma in first sensitive relapse. Patients who had primary refractory disease, resistant relapse, or who had relapsed two or more times had poor results, with less than 10% to 15% of the patients achieving long-term remission.11 There is a paucity of data with respect to the use of HDCT and transplantation in PTCL patients. Our objective in this study was to analyze whether salvage therapy with HDCT may overcome this initial negative effect of T-cell phenotyping. Results from this retrospective study of PTCL patients demonstrated a 3-year probability of survival of 36% and PFS of 32% in a group of heavily pretreated patients. These results are encouraging and are comparable with the results found for patients with B-cell histology. Vose et al21 reported a higher CR rate in 17 patients with PTCL who received an autologous bone marrow transplant as salvage therapy than the corresponding 24 patients with B-cell lymphomas (59% v 42%), but the survival was similar. In this trial, we identified pretransplant serum lactate dehydrogenase and IPI as important prognostic indicators for patients in relapse who might benefit the most from HDCT and transplantation. However, novel therapeutic approaches are needed for patients with worse prognoses. In that regard, allogeneic transplantation needs to be investigated further. Treatment failure in the group of patients who received allotransplants in this study was due to toxicity, and four of five patients who died were in CR. Using a less intensive nonmyeloablative regimen may improve the survival rate. The poor outcome for PTCL patients treated with conventional chemotherapy may be related to the distinct tumor biology of PTCL. Using conventional chemotherapy regimens, more than half of patients with PTCL relapsed. T-cell phenotyping loses its negative impact on the patient’s survival when treated with HDCT. Using this strategy as an upfront therapy for patients might improve their outcomes. Investigators need to evaluate this hypothesis. For that purpose, a randomized study at the University of Texas M.D. Anderson Cancer Center is ongoing, investigating HDCT and transplantation in PTCL patients in first remission.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
1 indicated a superior survival rate (P = .036) but not an improved PFS rate. A median follow-up of 43 months (range, 13 to 126 months) showed 13 patients (36%) were still alive with no evidence of disease. 
