Leukemia & Lymphoma, April 2014; 55(4): 727–729 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2013.858154
COMMENTARY
The problem with cyclophosphamide, doxorubicin, vincristine and prednisone for the treatment of peripheral T-cell lymphoma Roopesh Kansara & Kerry J. Savage Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada Peripheral T-cell lymphomas (PTCLs) account for approximately 10–15% of all non-Hodgkin lymphomas (NHLs). However, unlike their B-cell counterpart, where significant improvement in the overall survival (OS) has been achieved over the past decade, patients with PTCLs experience poor outcomes. CHOP combination chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone) has been our standard of care, largely based on trials that primarily enrolled patients with diffuse large B-cell lymphoma (DLBCL) [1]. Retrospective studies and a systematic review consistently report 5-year overall survival rates in the range of 30–40% [2–4]. Even worse outcomes are encountered in rare aggressive subtypes such as enteropathy-type T-cell lymphoma and those with multiple international prognostic index (IPI) risk factors [3]. Dose-intensive therapies, when compared to CHOP, have been largely disappointing [5], and the role of consolidative transplant remains controversial. Further, due to disease rarity, there have been few randomized studies evaluating alternative regimens compared to CHOP. The GOELAMS (Groupe Ouest-Est des Leucémies Aiguës Maladies du Sang) aimed to prospectively compare outcomes among patients with PTCL in a phase 3 randomized trial of eight cycles of 3-weekly CHOP versus alternating six cycles of VIP/ABVD (etoposide, ifosfamide, cisplatin/ doxorubicin, bleomycin, vinblastine and dacarbazine) [6]. Despite the selection of patients suitable to enter a clinical trial, outcomes were comparable to those of retrospective analyses, with a 2-year event-free survival (EFS) of only 41% (5-year overall survival [OS] ˜35%). This is also with the inclusion of some patients with limited stage disease as well as with ALK-positive (ALK-pos) anaplastic large cell lymphoma (ALCL), a subset that generally does well with CHOP. Whether adding additional chemotherapy to CHOP improves outcome in PTCLs remains unknown. The German Non-Hodgkin Lymphoma Group (DSHNHL) retrospectively evaluated the outcome of patients with PTCL treated with CHOP, with or without etoposide, at differing intervals (biweekly versus triweekly) and at various degrees of dose escalation of cyclophosphamide, doxorubicin and etoposide [7]. The best overall outcomes were noted for
ALK-positive ALCL, with a 3-year EFS and OS of 75.8% and 89.8%, respectively. The addition of etoposide was associated with an improved EFS in a select group of younger (⬍ 60 years) patients with a normal lactate dehydrogenase (LDH) level (3-year EFS 75% vs. 51%, p ⫽ 0.003); however, for patients without ALK-Pos ALCL, only a trend toward improved EFS was observed (p ⫽ 0.057), and there was no OS difference. The above data suggest that, apart from ALCL, anthracyclines may not be effective against PTCL. The International PTCL Study found no survival differences comparing the outcome of patients with PTCL treated with or without antracyclines [3]. Although the number of patients treated with non-anthracycline-based regimens is small, this group likely contained patients with comorbidities precluding the use of anthracylines, which should have favored the anthracycline group. A number of studies have explored the addition of novel agents to CHOP, including bortezomib [8], denileukin diftitox [9] and alemtuzumab [10–12], none of which have definitively shown improved outcomes over CHOP, and toxicities have been a major concern. Alemtuzumab is a humanized monoclonal antibody that selectively binds to the CD52 antigen which is expressed on normal T-cells, but due to broader expression on other immune cells, profound immunosuppression with opportunistic infections is not uncommon. Two phase 2 studies have been published evaluating CHOP and alemtuzumab [10,11], one of which was closed early due to two treatment-related deaths [11]. A more recent study evaluated CHO(E)P-14 (CHOP with or without etoposide) followed by consolidative alemtuzumab, but the 3-year EFS of the whole cohort was only 32%, improving to 42% in those who received alemtuzumab; however, the latter population was also selected for responders [12]. The present study by Ganjoo and colleagues on behalf of the Eastern Cooperative Oncology Group (E2404) evaluated bevacizumab (Avastin) in combination with CHOP (ACHOP) followed by maintenance bevacizumab in newly diagnosed patients with PTCL, excluding ALK-pos ALCL [13]. Bevacizumab is an antiangiogenic human
Correspondence: Dr. Kerry J. Savage, Medical Oncology, British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, BC, V5Z 4E6, Canada. Tel: 604877-6000. E-mail: [email protected] This commentary accompanies an article to be published in Leukemia & Lymphoma. Please refer to the table of contents of the print issue in which this commentary appears.
727
728 R. Kansara & K. J. Savage monoclonal antibody against the vascular endothelial growth factor (VEGF-A), which has been shown to be strongly expressed in PTCL and has been associated with a poor outcome [14], providing the rationale to study this combination in PTCLs. In total, 39 patients were eligible for the efficacy analysis and 44 patients were studied for toxicity. Only 23% of patients were able to complete all planned treatment. In addition, toxicity was also problematic, with 20% of patients developing a grade 2–4 cardiac event, which is detailed in a separate publication [15]. Left ventricular dysfunction (LVD) accounted for the majority; ventricular tachycardia was also seen. Most patients with LVD progressed to symptomatic heart failure. In addition, 23 patients developed grade 3 (n ⫽ 4) or 4 (n ⫽ 19) neutropenia, including eight events of febrile neutropenia. Overall, the 3-year progression-free survival (PFS) and OS were 16% and 37%, respectively, and thus similar, if not worse, than with CHOP alone. Interestingly, patients with angioimmunoblastic T-cell lymphoma (AITL) (n ⫽ 17) and ALK-negative (ALKneg) ALCL (n ⫽ 7) fared better than those with PTCL-not otherwise specified (NOS) (n ⫽ 15), with a 1-year PFS rate of 15%, 57% and 71%, respectively (p ⫽ 0.02). AILT is a richly vascular tumor, which may provide additional rationale to study antiangiogenic agents. For ALK-neg ALCL, other studies have supported that young, good-risk patients with ALK-neg ALCL have outcomes comparable to those with ALK-pos ALCL [16,17], which may explain the favorable survival of this group, although the clinical factors at diagnosis amongst the subtypes is not detailed in this study. Why anthracycline-based chemotherapy underperforms in PTCL is largely unknown. The multidrug resistance gene (MDR-1) and P-glycoprotein (P-gp) may be implicated. The MDR-1 gene encodes for P-gp, which is an adenosine triphosphate (ATP)-dependent transmembrane transporter responsible for intracellular drug efflux, and since anthracyclines and vinca alkaloids are substrates, this may explain multidrug resistance [18]. As such, several groups are exploring non-anthracycline based regimens in PTCL. The Southwest Oncology Group (SWOG) completed a phase 2 study of patients with PTCL utilizing agents that are not P-gp substrates. This protocol consisted of cisplatin, etoposide, gemcitabine and methylprednisolone (PEGS) [19]. Among patients with newly diagnosed PTCL, excluding patients with ALK-pos ALCL, a 2-year PFS of 14% and a 2-year OS of 36% was observed. Whether these poor results are explained by the lack of alkylators in this regimen, suboptimal dosing of gemcitabine or novel non-P-gp resistant pathways remains unknown. The Royal Marsden National Health Service (NHS) Foundation Trust and Cancer Research UK are currently evaluating another gemcitabine-based regimen (GEM-P) [20] in a randomized phase 2 study, compared to CHOP. In this study, gemcitabine is given on days 1, 8 and 15 on a 28-day cycle in combination with cisplatin and methylprednisolone (ClinicalTrials.gov/NCT10719835). The National Cancer Institute of Canada (NCIC) is currently conducting a phase 1 trial utilizing gemcitabine, dexamethasone and cisplatin (GDP, gemcitabine days 1 and 8 [21]) in combination with the histone deacetylase inhibitor romidepsin, which has recently been approved in the USA for patients with relapsed/refractory
PTCL (ClinicalTrials.gov/NCT01846390) with the goal of evaluating this combination in the up-front setting [22]. Significant challenges remain in the management of PTCLs. A more efficacious up-front combination needs to be identified in addition to an improved understanding of the molecular pathways that confer a survival advantage in PTCLs. Until major advances are made, the CHOP regimen will continue to be the standard backbone of therapy. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Fisher RI, Gaynor ER, Dahlberg S, et al. A phase III comparison of CHOP vs. m-BACOD vs. ProMACE-CytaBOM vs. MACOP-B in patients with intermediate- or high-grade non-Hodgkin’s lymphoma: results of SWOG-8516 (Intergroup 0067), the National High-Priority Lymphoma Study. Ann Oncol 1994;5:91–95. [2] Abouyabis AN, Shenoy PJ, Lechowicz MJ, et al. Incidence and outcomes of the peripheral T-cell lymphoma subtypes in the United States. Leuk Lymphoma 2008;49:2099–2107. [3] Vose J, Armitage J, Weisenburger D; International T-Cell Lymphoma Project. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 2008;26:4124–4130. [4] Savage KJ, Chhanabhai M, Gascoyne RD, et al. Characterization of peripheral T-cell lymphomas in a single North American institution by the WHO classification. Ann Oncol 2004;15:1467–1475. [5] Escalon MP, Liu NS, Yang Y, et al. Prognostic factors and treatment of patients with T-cell non-Hodgkin lymphoma. Cancer 2005;103: 2091–2098. [6] Simon A , Peoch M, Casassus P, et al. Upfront VIP-reinforcedABVD (VIP-rABVD) is not superior to CHOP/21 in newly diagnosed peripheral T cell lymphoma. Results of the randomized phase III trial GOELAMS-LTP95. Br J Haematology 2010;151: 159–166. [7] Schmitz N, Trumper L , Ziepert M , et al. Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group. Blood 2010;116: 3418 –3425 . [8] Lee J, Suh C, Kang HJ, et al. Phase I study of proteasome inhibitor bortezomib plus CHOP in patients with advanced, aggressive T-cell or NK/T-cell lymphoma. Ann Oncol 2008;19:2079–2083. [9] Foss FM, Sjak-Shie N, Goy A , et al. A multicenter phase II trial to determine the safety and efficacy of combination therapy with denileukin diftitox and cyclophosphamide, doxorubicin, vincristine and prednisone in untreated peripheral T-cell lymphoma: the CONCEPT study. Leuk Lymphoma 2013;54:1373–1379. [10] Kim JG, Sohn SK, Chae YS, et al. Alemtuzumab plus CHOP as frontline chemotherapy for patients with peripheral T-cell lymphomas: a phase II study. Cancer Chemother Pharmacol 2007;60:129–134. [11] Gallamini A , Zaja F, Patti C , et al. Alemtuzumab (Campath-1H) and CHOP chemotherapy as first-line treatment of peripheral T-cell lymphoma: results of a GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) prospective multicenter trial. Blood 2007;110:2316– 2323. [12] Binder C, Ziepert M, Pfreundschuh M, et al. CHO(E)P-14 followed by alemtuzumab consolidation in untreated peripheral T cell lymphomas: final analysis of a prospective phase II trial. Ann Hematol 2013;92:1521–1528. [13] Ganjoo K, Hong F, Horning SJ, et al. Bevacizumab and cyclophosphamide, doxorubicin, vincristine and prednisone in combination for patients with peripheral T-cell or natural killer cell neoplasms: an Eastern Cooperative Oncology study (E2404). Leuk Lymphoma. 2014;55:768–772. [14] Zhang W, Wang L, Zhou D, et al. Expression of tumor-associated macrophages and vascular endothelial growth factor correlates with poor prognosis of peripheral T-cell lymphoma, not otherwise specified. Leuk Lymphoma 2011;52:46–52.
Commentary 729 [15] Advani RH, Hong F, Horning SJ, et al. Cardiac toxicity associated with bevacizumab (Avastin) in combination with CHOP chemotherapy for peripheral T cell lymphoma in ECOG 2404 trial. Leuk Lymphoma 2011;53:718–720. [16] Savage KJ, Harris NL, Vose JM, et al. ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK⫹ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood 2008;111:5496–5504. [17] Sibon D, Fournier M, Briere J, et al. Long-term outcome of adults with systemic anaplastic large-cell lymphoma treated within the Groupe d’Etude des Lymphomes de l’Adulte trials. J Clin Oncol 2012;30:3939–3946. [18] Mahadevan D, List AF. Targeting the multidrug resistance-1 transporter in AML: molecular regulatio n and therapeutic strategies. Blood 2004;104:1940–1951.
[19] Mahadevan D, Unger JM, Spier CM, et al. Phase 2 trial of combined cisplatin, etoposide, gemcitabine, and methylprednisolone (PEGS) in peripheral T-cell non-Hodgkin lymphoma: Southwest Oncology Group Study S0350. Cancer 2013;119:371–379. [20] Arkenau HT, Chong G, Cunningham D, et al. Gemcitabine, cisplatin and methylprednisolone for the treatment of patients with peripheral T-cell lymphoma: the Royal Marsden Hospital experience. Haematologica 2007;92:271–272. [21] Crump M, Baetz T, Couban S, et al. Gemcitabine, dexamethasone, and cisplatin in patients with recurrent or refractory aggressive histology B-cell non-Hodgkin lymphoma: a phase II study by the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG). Cancer 2004;101:1835–1842. [22] Coiffier B, Pro B, Prince HM, et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol 2012;30:631–636.
Copyright of Leukemia & Lymphoma is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
COMMENTARY
The problem with cyclophosphamide, doxorubicin, vincristine and prednisone for the treatment of peripheral T-cell lymphoma Roopesh Kansara & Kerry J. Savage Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada Peripheral T-cell lymphomas (PTCLs) account for approximately 10–15% of all non-Hodgkin lymphomas (NHLs). However, unlike their B-cell counterpart, where significant improvement in the overall survival (OS) has been achieved over the past decade, patients with PTCLs experience poor outcomes. CHOP combination chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone) has been our standard of care, largely based on trials that primarily enrolled patients with diffuse large B-cell lymphoma (DLBCL) [1]. Retrospective studies and a systematic review consistently report 5-year overall survival rates in the range of 30–40% [2–4]. Even worse outcomes are encountered in rare aggressive subtypes such as enteropathy-type T-cell lymphoma and those with multiple international prognostic index (IPI) risk factors [3]. Dose-intensive therapies, when compared to CHOP, have been largely disappointing [5], and the role of consolidative transplant remains controversial. Further, due to disease rarity, there have been few randomized studies evaluating alternative regimens compared to CHOP. The GOELAMS (Groupe Ouest-Est des Leucémies Aiguës Maladies du Sang) aimed to prospectively compare outcomes among patients with PTCL in a phase 3 randomized trial of eight cycles of 3-weekly CHOP versus alternating six cycles of VIP/ABVD (etoposide, ifosfamide, cisplatin/ doxorubicin, bleomycin, vinblastine and dacarbazine) [6]. Despite the selection of patients suitable to enter a clinical trial, outcomes were comparable to those of retrospective analyses, with a 2-year event-free survival (EFS) of only 41% (5-year overall survival [OS] ˜35%). This is also with the inclusion of some patients with limited stage disease as well as with ALK-positive (ALK-pos) anaplastic large cell lymphoma (ALCL), a subset that generally does well with CHOP. Whether adding additional chemotherapy to CHOP improves outcome in PTCLs remains unknown. The German Non-Hodgkin Lymphoma Group (DSHNHL) retrospectively evaluated the outcome of patients with PTCL treated with CHOP, with or without etoposide, at differing intervals (biweekly versus triweekly) and at various degrees of dose escalation of cyclophosphamide, doxorubicin and etoposide [7]. The best overall outcomes were noted for
ALK-positive ALCL, with a 3-year EFS and OS of 75.8% and 89.8%, respectively. The addition of etoposide was associated with an improved EFS in a select group of younger (⬍ 60 years) patients with a normal lactate dehydrogenase (LDH) level (3-year EFS 75% vs. 51%, p ⫽ 0.003); however, for patients without ALK-Pos ALCL, only a trend toward improved EFS was observed (p ⫽ 0.057), and there was no OS difference. The above data suggest that, apart from ALCL, anthracyclines may not be effective against PTCL. The International PTCL Study found no survival differences comparing the outcome of patients with PTCL treated with or without antracyclines [3]. Although the number of patients treated with non-anthracycline-based regimens is small, this group likely contained patients with comorbidities precluding the use of anthracylines, which should have favored the anthracycline group. A number of studies have explored the addition of novel agents to CHOP, including bortezomib [8], denileukin diftitox [9] and alemtuzumab [10–12], none of which have definitively shown improved outcomes over CHOP, and toxicities have been a major concern. Alemtuzumab is a humanized monoclonal antibody that selectively binds to the CD52 antigen which is expressed on normal T-cells, but due to broader expression on other immune cells, profound immunosuppression with opportunistic infections is not uncommon. Two phase 2 studies have been published evaluating CHOP and alemtuzumab [10,11], one of which was closed early due to two treatment-related deaths [11]. A more recent study evaluated CHO(E)P-14 (CHOP with or without etoposide) followed by consolidative alemtuzumab, but the 3-year EFS of the whole cohort was only 32%, improving to 42% in those who received alemtuzumab; however, the latter population was also selected for responders [12]. The present study by Ganjoo and colleagues on behalf of the Eastern Cooperative Oncology Group (E2404) evaluated bevacizumab (Avastin) in combination with CHOP (ACHOP) followed by maintenance bevacizumab in newly diagnosed patients with PTCL, excluding ALK-pos ALCL [13]. Bevacizumab is an antiangiogenic human
Correspondence: Dr. Kerry J. Savage, Medical Oncology, British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, BC, V5Z 4E6, Canada. Tel: 604877-6000. E-mail: [email protected] This commentary accompanies an article to be published in Leukemia & Lymphoma. Please refer to the table of contents of the print issue in which this commentary appears.
727
728 R. Kansara & K. J. Savage monoclonal antibody against the vascular endothelial growth factor (VEGF-A), which has been shown to be strongly expressed in PTCL and has been associated with a poor outcome [14], providing the rationale to study this combination in PTCLs. In total, 39 patients were eligible for the efficacy analysis and 44 patients were studied for toxicity. Only 23% of patients were able to complete all planned treatment. In addition, toxicity was also problematic, with 20% of patients developing a grade 2–4 cardiac event, which is detailed in a separate publication [15]. Left ventricular dysfunction (LVD) accounted for the majority; ventricular tachycardia was also seen. Most patients with LVD progressed to symptomatic heart failure. In addition, 23 patients developed grade 3 (n ⫽ 4) or 4 (n ⫽ 19) neutropenia, including eight events of febrile neutropenia. Overall, the 3-year progression-free survival (PFS) and OS were 16% and 37%, respectively, and thus similar, if not worse, than with CHOP alone. Interestingly, patients with angioimmunoblastic T-cell lymphoma (AITL) (n ⫽ 17) and ALK-negative (ALKneg) ALCL (n ⫽ 7) fared better than those with PTCL-not otherwise specified (NOS) (n ⫽ 15), with a 1-year PFS rate of 15%, 57% and 71%, respectively (p ⫽ 0.02). AILT is a richly vascular tumor, which may provide additional rationale to study antiangiogenic agents. For ALK-neg ALCL, other studies have supported that young, good-risk patients with ALK-neg ALCL have outcomes comparable to those with ALK-pos ALCL [16,17], which may explain the favorable survival of this group, although the clinical factors at diagnosis amongst the subtypes is not detailed in this study. Why anthracycline-based chemotherapy underperforms in PTCL is largely unknown. The multidrug resistance gene (MDR-1) and P-glycoprotein (P-gp) may be implicated. The MDR-1 gene encodes for P-gp, which is an adenosine triphosphate (ATP)-dependent transmembrane transporter responsible for intracellular drug efflux, and since anthracyclines and vinca alkaloids are substrates, this may explain multidrug resistance [18]. As such, several groups are exploring non-anthracycline based regimens in PTCL. The Southwest Oncology Group (SWOG) completed a phase 2 study of patients with PTCL utilizing agents that are not P-gp substrates. This protocol consisted of cisplatin, etoposide, gemcitabine and methylprednisolone (PEGS) [19]. Among patients with newly diagnosed PTCL, excluding patients with ALK-pos ALCL, a 2-year PFS of 14% and a 2-year OS of 36% was observed. Whether these poor results are explained by the lack of alkylators in this regimen, suboptimal dosing of gemcitabine or novel non-P-gp resistant pathways remains unknown. The Royal Marsden National Health Service (NHS) Foundation Trust and Cancer Research UK are currently evaluating another gemcitabine-based regimen (GEM-P) [20] in a randomized phase 2 study, compared to CHOP. In this study, gemcitabine is given on days 1, 8 and 15 on a 28-day cycle in combination with cisplatin and methylprednisolone (ClinicalTrials.gov/NCT10719835). The National Cancer Institute of Canada (NCIC) is currently conducting a phase 1 trial utilizing gemcitabine, dexamethasone and cisplatin (GDP, gemcitabine days 1 and 8 [21]) in combination with the histone deacetylase inhibitor romidepsin, which has recently been approved in the USA for patients with relapsed/refractory
PTCL (ClinicalTrials.gov/NCT01846390) with the goal of evaluating this combination in the up-front setting [22]. Significant challenges remain in the management of PTCLs. A more efficacious up-front combination needs to be identified in addition to an improved understanding of the molecular pathways that confer a survival advantage in PTCLs. Until major advances are made, the CHOP regimen will continue to be the standard backbone of therapy. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Fisher RI, Gaynor ER, Dahlberg S, et al. A phase III comparison of CHOP vs. m-BACOD vs. ProMACE-CytaBOM vs. MACOP-B in patients with intermediate- or high-grade non-Hodgkin’s lymphoma: results of SWOG-8516 (Intergroup 0067), the National High-Priority Lymphoma Study. Ann Oncol 1994;5:91–95. [2] Abouyabis AN, Shenoy PJ, Lechowicz MJ, et al. Incidence and outcomes of the peripheral T-cell lymphoma subtypes in the United States. Leuk Lymphoma 2008;49:2099–2107. [3] Vose J, Armitage J, Weisenburger D; International T-Cell Lymphoma Project. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 2008;26:4124–4130. [4] Savage KJ, Chhanabhai M, Gascoyne RD, et al. Characterization of peripheral T-cell lymphomas in a single North American institution by the WHO classification. Ann Oncol 2004;15:1467–1475. [5] Escalon MP, Liu NS, Yang Y, et al. Prognostic factors and treatment of patients with T-cell non-Hodgkin lymphoma. Cancer 2005;103: 2091–2098. [6] Simon A , Peoch M, Casassus P, et al. Upfront VIP-reinforcedABVD (VIP-rABVD) is not superior to CHOP/21 in newly diagnosed peripheral T cell lymphoma. Results of the randomized phase III trial GOELAMS-LTP95. Br J Haematology 2010;151: 159–166. [7] Schmitz N, Trumper L , Ziepert M , et al. Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group. Blood 2010;116: 3418 –3425 . [8] Lee J, Suh C, Kang HJ, et al. Phase I study of proteasome inhibitor bortezomib plus CHOP in patients with advanced, aggressive T-cell or NK/T-cell lymphoma. Ann Oncol 2008;19:2079–2083. [9] Foss FM, Sjak-Shie N, Goy A , et al. A multicenter phase II trial to determine the safety and efficacy of combination therapy with denileukin diftitox and cyclophosphamide, doxorubicin, vincristine and prednisone in untreated peripheral T-cell lymphoma: the CONCEPT study. Leuk Lymphoma 2013;54:1373–1379. [10] Kim JG, Sohn SK, Chae YS, et al. Alemtuzumab plus CHOP as frontline chemotherapy for patients with peripheral T-cell lymphomas: a phase II study. Cancer Chemother Pharmacol 2007;60:129–134. [11] Gallamini A , Zaja F, Patti C , et al. Alemtuzumab (Campath-1H) and CHOP chemotherapy as first-line treatment of peripheral T-cell lymphoma: results of a GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) prospective multicenter trial. Blood 2007;110:2316– 2323. [12] Binder C, Ziepert M, Pfreundschuh M, et al. CHO(E)P-14 followed by alemtuzumab consolidation in untreated peripheral T cell lymphomas: final analysis of a prospective phase II trial. Ann Hematol 2013;92:1521–1528. [13] Ganjoo K, Hong F, Horning SJ, et al. Bevacizumab and cyclophosphamide, doxorubicin, vincristine and prednisone in combination for patients with peripheral T-cell or natural killer cell neoplasms: an Eastern Cooperative Oncology study (E2404). Leuk Lymphoma. 2014;55:768–772. [14] Zhang W, Wang L, Zhou D, et al. Expression of tumor-associated macrophages and vascular endothelial growth factor correlates with poor prognosis of peripheral T-cell lymphoma, not otherwise specified. Leuk Lymphoma 2011;52:46–52.
Commentary 729 [15] Advani RH, Hong F, Horning SJ, et al. Cardiac toxicity associated with bevacizumab (Avastin) in combination with CHOP chemotherapy for peripheral T cell lymphoma in ECOG 2404 trial. Leuk Lymphoma 2011;53:718–720. [16] Savage KJ, Harris NL, Vose JM, et al. ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK⫹ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood 2008;111:5496–5504. [17] Sibon D, Fournier M, Briere J, et al. Long-term outcome of adults with systemic anaplastic large-cell lymphoma treated within the Groupe d’Etude des Lymphomes de l’Adulte trials. J Clin Oncol 2012;30:3939–3946. [18] Mahadevan D, List AF. Targeting the multidrug resistance-1 transporter in AML: molecular regulatio n and therapeutic strategies. Blood 2004;104:1940–1951.
[19] Mahadevan D, Unger JM, Spier CM, et al. Phase 2 trial of combined cisplatin, etoposide, gemcitabine, and methylprednisolone (PEGS) in peripheral T-cell non-Hodgkin lymphoma: Southwest Oncology Group Study S0350. Cancer 2013;119:371–379. [20] Arkenau HT, Chong G, Cunningham D, et al. Gemcitabine, cisplatin and methylprednisolone for the treatment of patients with peripheral T-cell lymphoma: the Royal Marsden Hospital experience. Haematologica 2007;92:271–272. [21] Crump M, Baetz T, Couban S, et al. Gemcitabine, dexamethasone, and cisplatin in patients with recurrent or refractory aggressive histology B-cell non-Hodgkin lymphoma: a phase II study by the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG). Cancer 2004;101:1835–1842. [22] Coiffier B, Pro B, Prince HM, et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol 2012;30:631–636.
Copyright of Leukemia & Lymphoma is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
