- Email: [email protected]
High-Dose Therapy and Stem Cell Transplantation
High-Dose Therapy and Stem Cell Transplantation Pier Luigi Zinzani Results of conventional or high-dose chemotherapy for peripheral T-cell lymphoma (PTCL) are unsatisfactory, leaving a potential role for autologous or allogeneic stem cell transplantation. There are a number of retrospective studies and a few prospective studies on autologous transplantation for first-line PTCL treatment. Studies show that autologous transplant is feasible in relapsed and previously untreated patients, and efficacy is comparable to results in aggressive B-cell lymphomas. Allogeneic transplant may also have a role in relapsed PTCL, especially in the context of reducedintensity conditioning, which has decreased nonrelapse mortality. However, it is unclear whether there is a role for allogeneic transplant as a frontline treatment option. Semin Hematol 47:S15-S17. © 2010 Published by Elsevier Inc.
AUTOLOGOUS STEM CELL TRANSPLANT
A
number of retrospective studies shed light on the roll of autologous stem cell transplantation (autotransplantation) in peripheral T-cell lymphoma (PTCL). Overall survival in these studies ranges between 50% to 70% at 3 or 5 years with different conditioning regimens (Table 1).1– 6 Prospective data exist on almost 200 patients treated with autotransplant as a first-line treatment (Table 2).7–9 The treatment regimens varied, but all included an induction phase, consolidation with a high-dose regimen, and then autologous stem cell transplantation. The transplantation rates are 73%7,8 and 41%9 in these trials. The overall response rates (ORR) were 81%, 69%, and 59%. Overall survival rates at 3 years are 73%7 and 63%8 and 39%9 at 4 years. The Italian group10 and the German group11 have also provided some prospective experience. The two Italian phase II studies10 used different therapeutic approaches. One used MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin) and then high-dose therapy with cytarabine and mitoxantrone before mobilization of the peripheral stem cells, followed by BEAM (carmustine, etoposide, cytarabine, and melphalan) and autotransplant. The University of Bologna, Bologna, Italy. CONFLICT OF INTEREST STATEMENT: Dr. Zinzani has no conflicts of interest to disclose. Address correspondence to Pier Luigi Zinzani, MD, PhD, Bologna University, Policlinico S Orsola–Malpighi Via Massarenti 9, Bologna, Italy 40138. E-mail: [email protected] 0037-1963/10/$ - see front matter © 2010 Published by Elsevier Inc. doi:10.1053/j.seminhematol.2010.01.017
second study consisted of two cycles of APO (doxorubicin, prednisone, and vincristine) and then two cycles of DHAP (dexamethasone, cytarabine, and cisplatin), with cyclophosphamide, cisplatin, and etoposide for stem cell mobilization, and high-dose melphalan and mitoxantrone as conditioning before autotransplant. These trials enrolled 62 patients with a median age of 43 years. Eighty-two percent had stage III or IV disease, 52% had two or more extranodal sites, and 71% had an International Prognostic Index (IPI) score of 2 or 3. Twenty-eight patients had PTCL unspecified, 19 patients had ALK⫹ anaplastic large cell lymphoma (ALCL), 10 had angioimmunoblastic T-cell lymphoma (AILT), four had ALK– ALCL, and one had intestinal lymphoma. Only 46 of 62 patients went on to high-dose treatment and autotransplant. Almost one third of the patients dropped out of the second part of the study due to progressive disease. There was a significant difference in overall survival between ALK⫹ ALCL and nonALK⫹ subtype patients (62% v 21%, respectively, at 12 years). The differences in disease-free survival and event-free survival were also significantly better for those with ALK⫹ ALCL (54% v 18% and 48% v 24%, respectively). The median follow-up was 76 months. Univariate and multivariate analyses showed that status before autotransplant is the most important prognostic factor influencing outcome.10 ALK positivity and IPI score also reached significance in the univariate analysis, but bone marrow involvement, number of extranodal sites, and study protocol did not. In the German study,11 patients received six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and then dexaBEAM (dexamethasone, carmustine, etoposide, cytarabine, and melphalan) or ESHAP (etoposide, methylprednisolone, cispla-
Seminars in Hematology, Vol 47, No 2, Suppl 1, April 2010, pp S15-S17
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P.L. Zinzani
Table 1. Retrospective Studies on Autologous Transplantation as First-Line Treatment
Study
n
CR
OS
PTCL Subtypes Included
Rodriguez, 20071 Rodriguez, 20072 Feyler, 20073 Kyriakou, 20084 Khouri, 20085 Yang, 20096
19 74 64 146 79 64
79% ND ND 70% ND ND
60% (5 yr) 68% (5 yr) 53% (3 yr) 59% (4 yr) not reached at 64 mo 53% (3 yr)
Only AILT, subgroup Including ALCL Including ALK⫹ALCL Only AILT, subgroup Including ALCL, subgroup Only PTCLu
Abbreviations: AILT, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large cell lymphoma; CR, complete response; DFS, diseasefree survival; ND, no data; OS, overall survival; PTCLu, peripheral T-cell lymphoma unspecified.
tin, and cytarabine) for collection of peripheral stem cells. Patients were then conditioned with total body irradiation before autotransplantation. The study included 83 patients: 39% had PTCL unspecified, 33% had AILT, 16% had ALK⫺ ALCL, 6% had intestinal lymphoma, 5% had nasal-type lymphoma, and 2% had hepatosplenic lymphoma. Most patients (75%) had advanced disease (stage III/IV), and according to IPI, 35% had intermediate-low-risk disease, 45% had intermediate-high-risk disease, and 6% had high-risk disease. After six cycles of CHOP, 39% of patients achieved a complete response (CR) and 40% achieved a partial response (PR); 18 patients discontinued the study due to progressive disease. After stem cell mobilization, the CR rate was 60%, but another 10 patients dropped out of the study before completing transplant due to progressive disease. A total of 55 patients underwent autologous transplant, of whom 87% achieved CR and 17 died after a median follow-up of 12 months. Of the 28 patients who did not undergo autotransplant, 23 died, two achieved CR, and three are alive with their disease. Transplanted patients had a significantly better overall survival than those who did not receive transplant. The estimated 3-year overall survival rate is 48%, while the estimated 3-year progression-free and disease-free survival rates are 36% and 53%, respectively.
ALLOGENEIC STEM CELL TRANSPLANT There is also rationale for allogeneic stem cell transplant (allotransplant) in T-cell lymphoma. Results of
conventional or high-dose chemotherapy are still largely unsatisfactory. Additionally, T cells can be a good target for donor-derived immune cells, the so-called “graftversus-lymphoma” effect, and allogeneic grafts are free from tumor cell contamination. A retrospective study of myeloablative allotransplant from related and unrelated donors in non-Hodgkin lymphoma patients12 showed that treatment-related mortality was approximately 40%. However, when overall survival was stratified according to histologic subtype (PTCL, diffuse large B-cell lymphoma, natural killer [NK]/T-cell lymphoma, and other aggressive lymphomas), PTCL had the highest overall survival rate. Reduced-intensity conditioning may be a possible solution to decrease allotransplant treatment-related mortality. Data from patients treated with a reduced-intensity conditioning plan including thiotepa, fludarabine, and cyclophosphamide13 showed an estimated overall survival rate of 80%.14 Fifteen of the 17 PTCL patients were chemosensitive to their last regimen. Progression-free survival at 3 years was 60%, and nonrelapse mortality at 2 years was 6%. Another small study of allogeneic transplant after reduced-intensity conditioning or myeloablation in relapsed aggressive T-cell lymphoma included data from 14 patients (five PTCL unspecified, two mycosis fungoides, and seven T-cell lymphoblastic lymphoma). Patients received either a fludarabine-based reduced intensity conditioning regimen or total body irradiation– based or a busulfan-based myeloablative regimen.
Table 2. Prospective PTCL-Restricted Studies on Autologous Transplantation as First-Line Treatment
Study 20077
Rodriguez, D’Amore, 20068 Mercadal, 20089
Pts (n)
Age (yr)
Tx Rate (%)
CR/PR (%)
TRM (%)
26 121 41
44 55 47
73 73 41
81 69 59
0 4 ND
OS
FU
73% (3 yr) 35 mo 63% (3 yr) 2.5 yr 39% (4 yr) 3.2 yr
Abbreviations: CR/PR, complete response/partial response; FU, follow-up; ND, no data; OS, overall survival; pts, patients; Tx, transplantation; TRM, treatment-related mortality.
High-dose therapy and stem cell transplantation
The results have been submitted by Zinzani et al for publication. A 5-year-follow-up of the phase II prospective multicenter study on reduced intensity conditioning allogeneic transplant from sibling donors in relapsed lymphomas15 is showing encouraging results in the 38 PTCL patients. The update has not yet been published.
CONCLUSIONS Autologous stem cell transplantation is feasible in relapsed and previously untreated patients, and efficacy data is comparable to data for aggressive B-cell lymphomas. However, it is still a controversial approach as upfront therapy, and about 30% of patients do not reach autotransplantation due to progressive disease. Chemosensitivity and IPI scores seem to predict outcome for patients who are candidates for autotransplant. Data from all of these trials must still be validated in randomized studies. Reduced-intensity conditioning for allotransplant has decreased the nonrelapse mortality, and results for disease control in relapsed patients have been promising. However, it is still unclear whether there is a role for allotransplant as a frontline treatment option. It may be suitable for a particular subset of patients, but new agents may hold more appeal.
REFERENCES 1. Rodriguez J, Conde E, Gutierrez A, et al. The results of consolidation with autologous stem-cell transplantation in patients with peripheral T-cell lymphoma (PTCL) in first complete remission: the Spanish Lymphoma and Autologous Transplantation Group experience. Ann Oncol. 2007;18:652–7. 2. Rodriguez J, Conde E, Gutierrez A, et al. Prolonged survival of patients with angioimmunoblastic T-cell lymphoma after high-dose chemotherapy and autologous stem cell transplantation: the GELTAMO experience. Eur J Haematol. 2007;78:290 – 6. 3. Feyler S, Prince HM, Pearce R, et al. The role of high-dose therapy and stem cell rescue in the management of T-cell malignant lymphomas: a BSBMT and ABMTRR study. Bone Marrow Transplant. 2007;40:443–50. 4. Kyriakou C, Canals C, Goldstone A, et al. High-dose therapy and autologous stem-cell transplantation in angioimmunoblastic lymphoma: complete remission at transplantation is the major determinant of Outcome-Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2008;26:218 –24.
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5. Khouri IF, Lopez A, Okoroji G-J, et al. Myeloablative chemotherapy for T-cell lymphoma: a case for autologous stem cell transplantation (auto) in first remission [abstr 1141]. Blood. 2008;112:417. 6. Yang DH, Kim WS, Kim SJ, et al. Prognostic factors and clinical outcomes of high-dose chemotherapy followed by autologous stem cell transplantation in patients with peripheral T cell lymphoma, unspecified: complete remission at transplantation and the prognostic index of peripheral T cell lymphoma are the major factors predictive of outcome. Biol Blood Marrow Transplant. 2009; 15:118 –25. 7. Rodriguez J, Conde E, Gutierrez A, et al. Frontline autologous stem cell transplantation in high-risk peripheral T-cell lymphoma: a prospective study from the Gel-Tamo Study Group. Eur J Haematol. 2007;79:32– 8. 8. d’Amore F, Relander T, Lauritzen G, et al. Dose-dense induction followed by autologous stem cell transplant (ASCT) as 1st line treatment in peripheral T-cell lymphomas (PTCL)—a phase II study of the Nordic Lymphoma Group (NLG) [abstr 401]. Blood. 2006;108:123a. 9. Mercadal S, Briones J, Xicoy B, et al. Intensive chemotherapy (high-dose CHOP/ESHAP regimen) followed by autologous stem-cell transplantation in previously untreated patients with peripheral T-cell lymphoma. Ann Oncol. 2008;19:958 – 63. 10. Corradini P, Tarella C, Zallio F, et al. Long-term follow-up of patients with peripheral T-cell lymphomas treated up-front with high-dose chemotherapy followed by autologous stem cell transplantation. Leukemia. 2006;20:1533– 8. 11. Reimer P, Rudiger T, Geissinger E, et al. Autologous stem-cell transplantation as first-line therapy in peripheral T-cell lymphomas: results of a prospective multicenter study. J Clin Oncol. 2009;27:106 –13. 12. Kim SW, Tanimoto TE, Hirabayashi N, et al. Myeloablative allogeneic hematopoietic stem cell transplantation for non-Hodgkin lymphoma: a nationwide survey in Japan. Blood. 2006;108:382–9. 13. Corradini P, Tarella C, Olivieri A, et al. Reduced-intensity conditioning followed by allografting of hematopoietic cells can produce clinical and molecular remissions in patients with poor-risk hematologic malignancies. Blood. 2002;99:75– 82. 14. Corradini P, Dodero A, Zallio F, et al. Graft-versus-lymphoma effect in relapsed peripheral T-cell non-Hodgkin’s lymphomas after reduced-intensity conditioning followed by allogeneic transplantation of hematopoietic cells. J Clin Oncol. 2004;22:2172–6. 15. Corradini P, Dodero A, Farina L, et al. Allogeneic stem cell transplantation following reduced-intensity conditioning can induce durable clinical and molecular remissions in relapsed lymphomas: pre-transplant disease status and histotype heavily influence outcome. Leukemia. 2007;21:2316 –23.
AUTOLOGOUS STEM CELL TRANSPLANT
A
number of retrospective studies shed light on the roll of autologous stem cell transplantation (autotransplantation) in peripheral T-cell lymphoma (PTCL). Overall survival in these studies ranges between 50% to 70% at 3 or 5 years with different conditioning regimens (Table 1).1– 6 Prospective data exist on almost 200 patients treated with autotransplant as a first-line treatment (Table 2).7–9 The treatment regimens varied, but all included an induction phase, consolidation with a high-dose regimen, and then autologous stem cell transplantation. The transplantation rates are 73%7,8 and 41%9 in these trials. The overall response rates (ORR) were 81%, 69%, and 59%. Overall survival rates at 3 years are 73%7 and 63%8 and 39%9 at 4 years. The Italian group10 and the German group11 have also provided some prospective experience. The two Italian phase II studies10 used different therapeutic approaches. One used MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin) and then high-dose therapy with cytarabine and mitoxantrone before mobilization of the peripheral stem cells, followed by BEAM (carmustine, etoposide, cytarabine, and melphalan) and autotransplant. The University of Bologna, Bologna, Italy. CONFLICT OF INTEREST STATEMENT: Dr. Zinzani has no conflicts of interest to disclose. Address correspondence to Pier Luigi Zinzani, MD, PhD, Bologna University, Policlinico S Orsola–Malpighi Via Massarenti 9, Bologna, Italy 40138. E-mail: [email protected] 0037-1963/10/$ - see front matter © 2010 Published by Elsevier Inc. doi:10.1053/j.seminhematol.2010.01.017
second study consisted of two cycles of APO (doxorubicin, prednisone, and vincristine) and then two cycles of DHAP (dexamethasone, cytarabine, and cisplatin), with cyclophosphamide, cisplatin, and etoposide for stem cell mobilization, and high-dose melphalan and mitoxantrone as conditioning before autotransplant. These trials enrolled 62 patients with a median age of 43 years. Eighty-two percent had stage III or IV disease, 52% had two or more extranodal sites, and 71% had an International Prognostic Index (IPI) score of 2 or 3. Twenty-eight patients had PTCL unspecified, 19 patients had ALK⫹ anaplastic large cell lymphoma (ALCL), 10 had angioimmunoblastic T-cell lymphoma (AILT), four had ALK– ALCL, and one had intestinal lymphoma. Only 46 of 62 patients went on to high-dose treatment and autotransplant. Almost one third of the patients dropped out of the second part of the study due to progressive disease. There was a significant difference in overall survival between ALK⫹ ALCL and nonALK⫹ subtype patients (62% v 21%, respectively, at 12 years). The differences in disease-free survival and event-free survival were also significantly better for those with ALK⫹ ALCL (54% v 18% and 48% v 24%, respectively). The median follow-up was 76 months. Univariate and multivariate analyses showed that status before autotransplant is the most important prognostic factor influencing outcome.10 ALK positivity and IPI score also reached significance in the univariate analysis, but bone marrow involvement, number of extranodal sites, and study protocol did not. In the German study,11 patients received six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and then dexaBEAM (dexamethasone, carmustine, etoposide, cytarabine, and melphalan) or ESHAP (etoposide, methylprednisolone, cispla-
Seminars in Hematology, Vol 47, No 2, Suppl 1, April 2010, pp S15-S17
S15
S16
P.L. Zinzani
Table 1. Retrospective Studies on Autologous Transplantation as First-Line Treatment
Study
n
CR
OS
PTCL Subtypes Included
Rodriguez, 20071 Rodriguez, 20072 Feyler, 20073 Kyriakou, 20084 Khouri, 20085 Yang, 20096
19 74 64 146 79 64
79% ND ND 70% ND ND
60% (5 yr) 68% (5 yr) 53% (3 yr) 59% (4 yr) not reached at 64 mo 53% (3 yr)
Only AILT, subgroup Including ALCL Including ALK⫹ALCL Only AILT, subgroup Including ALCL, subgroup Only PTCLu
Abbreviations: AILT, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large cell lymphoma; CR, complete response; DFS, diseasefree survival; ND, no data; OS, overall survival; PTCLu, peripheral T-cell lymphoma unspecified.
tin, and cytarabine) for collection of peripheral stem cells. Patients were then conditioned with total body irradiation before autotransplantation. The study included 83 patients: 39% had PTCL unspecified, 33% had AILT, 16% had ALK⫺ ALCL, 6% had intestinal lymphoma, 5% had nasal-type lymphoma, and 2% had hepatosplenic lymphoma. Most patients (75%) had advanced disease (stage III/IV), and according to IPI, 35% had intermediate-low-risk disease, 45% had intermediate-high-risk disease, and 6% had high-risk disease. After six cycles of CHOP, 39% of patients achieved a complete response (CR) and 40% achieved a partial response (PR); 18 patients discontinued the study due to progressive disease. After stem cell mobilization, the CR rate was 60%, but another 10 patients dropped out of the study before completing transplant due to progressive disease. A total of 55 patients underwent autologous transplant, of whom 87% achieved CR and 17 died after a median follow-up of 12 months. Of the 28 patients who did not undergo autotransplant, 23 died, two achieved CR, and three are alive with their disease. Transplanted patients had a significantly better overall survival than those who did not receive transplant. The estimated 3-year overall survival rate is 48%, while the estimated 3-year progression-free and disease-free survival rates are 36% and 53%, respectively.
ALLOGENEIC STEM CELL TRANSPLANT There is also rationale for allogeneic stem cell transplant (allotransplant) in T-cell lymphoma. Results of
conventional or high-dose chemotherapy are still largely unsatisfactory. Additionally, T cells can be a good target for donor-derived immune cells, the so-called “graftversus-lymphoma” effect, and allogeneic grafts are free from tumor cell contamination. A retrospective study of myeloablative allotransplant from related and unrelated donors in non-Hodgkin lymphoma patients12 showed that treatment-related mortality was approximately 40%. However, when overall survival was stratified according to histologic subtype (PTCL, diffuse large B-cell lymphoma, natural killer [NK]/T-cell lymphoma, and other aggressive lymphomas), PTCL had the highest overall survival rate. Reduced-intensity conditioning may be a possible solution to decrease allotransplant treatment-related mortality. Data from patients treated with a reduced-intensity conditioning plan including thiotepa, fludarabine, and cyclophosphamide13 showed an estimated overall survival rate of 80%.14 Fifteen of the 17 PTCL patients were chemosensitive to their last regimen. Progression-free survival at 3 years was 60%, and nonrelapse mortality at 2 years was 6%. Another small study of allogeneic transplant after reduced-intensity conditioning or myeloablation in relapsed aggressive T-cell lymphoma included data from 14 patients (five PTCL unspecified, two mycosis fungoides, and seven T-cell lymphoblastic lymphoma). Patients received either a fludarabine-based reduced intensity conditioning regimen or total body irradiation– based or a busulfan-based myeloablative regimen.
Table 2. Prospective PTCL-Restricted Studies on Autologous Transplantation as First-Line Treatment
Study 20077
Rodriguez, D’Amore, 20068 Mercadal, 20089
Pts (n)
Age (yr)
Tx Rate (%)
CR/PR (%)
TRM (%)
26 121 41
44 55 47
73 73 41
81 69 59
0 4 ND
OS
FU
73% (3 yr) 35 mo 63% (3 yr) 2.5 yr 39% (4 yr) 3.2 yr
Abbreviations: CR/PR, complete response/partial response; FU, follow-up; ND, no data; OS, overall survival; pts, patients; Tx, transplantation; TRM, treatment-related mortality.
High-dose therapy and stem cell transplantation
The results have been submitted by Zinzani et al for publication. A 5-year-follow-up of the phase II prospective multicenter study on reduced intensity conditioning allogeneic transplant from sibling donors in relapsed lymphomas15 is showing encouraging results in the 38 PTCL patients. The update has not yet been published.
CONCLUSIONS Autologous stem cell transplantation is feasible in relapsed and previously untreated patients, and efficacy data is comparable to data for aggressive B-cell lymphomas. However, it is still a controversial approach as upfront therapy, and about 30% of patients do not reach autotransplantation due to progressive disease. Chemosensitivity and IPI scores seem to predict outcome for patients who are candidates for autotransplant. Data from all of these trials must still be validated in randomized studies. Reduced-intensity conditioning for allotransplant has decreased the nonrelapse mortality, and results for disease control in relapsed patients have been promising. However, it is still unclear whether there is a role for allotransplant as a frontline treatment option. It may be suitable for a particular subset of patients, but new agents may hold more appeal.
REFERENCES 1. Rodriguez J, Conde E, Gutierrez A, et al. The results of consolidation with autologous stem-cell transplantation in patients with peripheral T-cell lymphoma (PTCL) in first complete remission: the Spanish Lymphoma and Autologous Transplantation Group experience. Ann Oncol. 2007;18:652–7. 2. Rodriguez J, Conde E, Gutierrez A, et al. Prolonged survival of patients with angioimmunoblastic T-cell lymphoma after high-dose chemotherapy and autologous stem cell transplantation: the GELTAMO experience. Eur J Haematol. 2007;78:290 – 6. 3. Feyler S, Prince HM, Pearce R, et al. The role of high-dose therapy and stem cell rescue in the management of T-cell malignant lymphomas: a BSBMT and ABMTRR study. Bone Marrow Transplant. 2007;40:443–50. 4. Kyriakou C, Canals C, Goldstone A, et al. High-dose therapy and autologous stem-cell transplantation in angioimmunoblastic lymphoma: complete remission at transplantation is the major determinant of Outcome-Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2008;26:218 –24.
S17
5. Khouri IF, Lopez A, Okoroji G-J, et al. Myeloablative chemotherapy for T-cell lymphoma: a case for autologous stem cell transplantation (auto) in first remission [abstr 1141]. Blood. 2008;112:417. 6. Yang DH, Kim WS, Kim SJ, et al. Prognostic factors and clinical outcomes of high-dose chemotherapy followed by autologous stem cell transplantation in patients with peripheral T cell lymphoma, unspecified: complete remission at transplantation and the prognostic index of peripheral T cell lymphoma are the major factors predictive of outcome. Biol Blood Marrow Transplant. 2009; 15:118 –25. 7. Rodriguez J, Conde E, Gutierrez A, et al. Frontline autologous stem cell transplantation in high-risk peripheral T-cell lymphoma: a prospective study from the Gel-Tamo Study Group. Eur J Haematol. 2007;79:32– 8. 8. d’Amore F, Relander T, Lauritzen G, et al. Dose-dense induction followed by autologous stem cell transplant (ASCT) as 1st line treatment in peripheral T-cell lymphomas (PTCL)—a phase II study of the Nordic Lymphoma Group (NLG) [abstr 401]. Blood. 2006;108:123a. 9. Mercadal S, Briones J, Xicoy B, et al. Intensive chemotherapy (high-dose CHOP/ESHAP regimen) followed by autologous stem-cell transplantation in previously untreated patients with peripheral T-cell lymphoma. Ann Oncol. 2008;19:958 – 63. 10. Corradini P, Tarella C, Zallio F, et al. Long-term follow-up of patients with peripheral T-cell lymphomas treated up-front with high-dose chemotherapy followed by autologous stem cell transplantation. Leukemia. 2006;20:1533– 8. 11. Reimer P, Rudiger T, Geissinger E, et al. Autologous stem-cell transplantation as first-line therapy in peripheral T-cell lymphomas: results of a prospective multicenter study. J Clin Oncol. 2009;27:106 –13. 12. Kim SW, Tanimoto TE, Hirabayashi N, et al. Myeloablative allogeneic hematopoietic stem cell transplantation for non-Hodgkin lymphoma: a nationwide survey in Japan. Blood. 2006;108:382–9. 13. Corradini P, Tarella C, Olivieri A, et al. Reduced-intensity conditioning followed by allografting of hematopoietic cells can produce clinical and molecular remissions in patients with poor-risk hematologic malignancies. Blood. 2002;99:75– 82. 14. Corradini P, Dodero A, Zallio F, et al. Graft-versus-lymphoma effect in relapsed peripheral T-cell non-Hodgkin’s lymphomas after reduced-intensity conditioning followed by allogeneic transplantation of hematopoietic cells. J Clin Oncol. 2004;22:2172–6. 15. Corradini P, Dodero A, Farina L, et al. Allogeneic stem cell transplantation following reduced-intensity conditioning can induce durable clinical and molecular remissions in relapsed lymphomas: pre-transplant disease status and histotype heavily influence outcome. Leukemia. 2007;21:2316 –23.