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Peripheral T-cell lymphoma: The role of hematopoietic stem cell transplantation
Critical Reviews in Oncology/Hematology, 2, 89, pages 248 - 261
Peripheral T-cell lymphoma (PTCL) is a rare and heterogeneous group of non-Hodgkin lymphomas (NHLs). Whereas the incidence of the disease appears to increase during last decades and the prognosis remains dramatically poor, so far no standard treatment has been established. High-dose chemotherapy and autologous stem cell transplantation (HDT–ASCT) has been proven effective in relapsed PTCL, while retrospective studies have shown a survival benefit as first-line treatment in some subsets of PTCL patients.
However, given disease rarity, there is a paucity of randomized trials in both upfront and relapse setting. Here, we critically evaluated eligible prospective and retrospective studies that address the role of ASCT in treatment of PTCL, with respect to quality of design and performance. Additionally, the role of allogeneic transplantation has been reviewed.
The comparison of ASCT with novel agents that emerge or the combination of both, are to be ascertained via prospective randomized trials in this field.
Abbreviations: AaIPI - age-adjusted IPI, ACVBP - doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone, intrathecal methotrexate, ALCL - anaplastic large cell lymphoma, ALK - anaplastic lymphoma kinase, Allo-SCT - allogeneic stem cell transplantation, AITL - angioimmunoblastic T-cell lymphoma, ATG - anti-thymocyte globulin, ASCT - autologous stem cell transplantation, BEAC - BCNU, etoposide, cytarabin, cyclophosphamide, BEAM - BCNU, etoposide, cytarabin, melphalan, BCNU - carmustine, BEC - busulfan, etoposide, cyclophosphamide, B - busulfan, C - cyclophosphamide, Cyt - cytarabin, CR - complete response (CR1/2 first/second complete remission), CVB - BCNU, etoposide, cyclophosphamide, CEOP - cyclophosphamide, epirubicin, vincristine, prednisone, CHOEP - cyclophosphamide, vincristine, doxorubicin, etoposide, prednisone, CTCL - cutaneous T-cell lymphoma, CVB/CBV - BCNU, etoposide, cyclophosphamide, DFS - disease-free survival, DHAP - dexamethasone, cytarabine, cisplatin, DLBL - diffuse large B-cell lymphoma, EATL - enteropathy-associated T-cell lymphoma, ECVBP - epirubicin, cyclophosphamide, vindesine, bleomycin, prednisone, EFS - event-free survival, E - etoposide, Flu - fludarabine, GVHD - graft-versus-host disease, HSTL - hepatosplenic T-cell lymphoma, IFE - ifosfamide, etoposide, ICE - ifosfamide, carboplatin, etoposide, IPI - international prognostic index, ITTP - intention to treat population, MA/MAC - myeloablative conditioning, MCEC - ranimustine, cyclophosphamide, etoposide, carboplatin, Mito - mitoxantrone, Mel - melphalan, NK/T - natural killer-cell/T-cell leukemia/lymphoma, NK - natural killer cell, NRM - non-relapse mortality, ORR - overall response rate, OS - overall survival, P - cisplatin, PFS - progression-free survival, ProMACE-CytBOM - prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide–cytarabine, bleomycin, vincristine, methotrexate, PR - partial remission, PIF - primary induction failure, RIC - reduced intensity conditioning, TBI - total body irradiation, Thio - thiotepa, TTF - time to treatment failure, TRM - treatment-related mortality, W - weeks, Y - year.
Keywords: Peripheral T-cell lymphoma, PTCL, Autologous stem cell transplantation, ASCT, High-dose chemotherapy, Transplantation.
Peripheral T-cell lymphomas (PTCLs) belong to non-Hodgkin lymphomas (NHLs) and constitute a heterogeneous group of lymphomas. This group accounts approximately 10% of aggressive NHLs in Western countries  and . The incidence of PTCL is rising with nearly 3 times more cases diagnosed in the USA in 2005 than in 1992, whereas 69,740 estimated new cases of NHLs and 19,020 estimated deaths by the disease in 2013  and . The most recent World Health Organization of Tumors of Hematopoietic and Lymphoid Tissues classification recognizes three most common distinct histopathologic subtypes: peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), which is the most prevalent group of PTCLs (30–60%)  , the angioimmunoblastic T-cell lymphoma (AITL) and the anaplastic large cell lymphoma (ALCL), where the fusion protein nucleophosmin anaplastic lymphoma kinase (ALK) could be expressed (ALK+) or not (ALK−)  ( Table 1 ).
|WHO 2008 classification of T-cell lymphomas|
|Adult T-cell leukemia/lymphoma|
|Hydroa vacciniforme-like lymphoma|
|Extranodal NK/T-cell lymphoma, nasal type|
|Enteropathy-associated T-cell lymphoma|
|Hepatosplenic T-cell lymphoma|
|Primary cutaneous CD30-positive T-cell lymphoproliferative disorders|
|Primary cutaneous anaplastic large cell lymphoma|
|Primary cutaneous peripheral T-cell lymphomas, rare subtypes|
|Primary cutaneous gamma-delta T-cell lymphoma|
|Primary cutaneous CD38 aggressive epidermotropic T-cell lymphoma|
|Primary cutaneous CD4+ small/medium T-cell lymphoma|
|Peripheral T-cell lymphoma, not otherwise specified (NOS)|
|Angioimmunoblastic T-cell lymphoma|
|Anaplastic large cell lymphoma, ALK+|
|Anaplastic large cell lymphoma, ALK−|
To date, there are not specific immunophenotyping characteristics or genetic features well established. The IPI system that has been used for prediction of long-term survival and as prognostic tool in both B- and T-cell lymphomas, has not shown the same value in certain subtypes of PTCLs  and . Recently, a prognostic system in PTCL-NOS has been developed based on the results of a retrospective multicenter study  . This system utilizes four clinical variables (age, PS, LDH, and bone marrow infiltration) and has not been evaluated in prospective randomized trials yet.
In contrast to B-cell lymphomas, patients with PTCLs exhibit more aggressive clinical features, B-symptoms, extranodal disease and other markers of advanced disease which are associated also with poor prognosis, such as increased serum lactate dehydrogenase (LDH), bulky disease, elevated Ki-67, over-expression of p53 , , , , and . Compared to the corresponding aggressive B-cell lymphomas, the prognosis of PTCLs is dramatically inferior, with the notable exception of ALCL ALK (+). Current conventional treatment regimens have not achieved so far, to improve considerably the outcome. The prognosis of PTCLs is very poor, with a 5-year disease free survival below 30%, treated with standard chemotherapy consisted of second and third-generation agents  and .
The exact role of high dose therapy (HDT) and autologous stem cell support (ASCT) remains undefined. Although that several retrospective and some prospective studies of ACST have shown improved outcome in PTCLs patients, there are reports with inconsistent results. This mainly results from small size of the patient population in clinical trials, the heterogeneity of PTCLs and the enrollment of patients with ALK (+) lymphomas in some trials, which present a more favorable outcome. The timing of ASCT in the treatment of PTCLs, i.e., either in the frontline setting or in relapsed disease is still a debatable issue; ASCT, the standard treatment for relapsed diffuse large B-cell lymphoma (DBLCL) has shown effectiveness for PTCL in several retrospective studies as salvage treatment but also as part of upfront treatment in many prospective studies.
With respect to allogeneic stem cell transplantation (allo-SCT), there are limited data for its usage in patients with PTCL, as it is reserved for relapsed, heavily pre-treated, and chemo-refractory patients. In an attempt to examine the role of ASCT and allo-SCT in the treatment of PTCL and to clarify if these therapeutic strategies are able finally to improve the clinical outcome, we reviewed available prospective and retrospective studies.
1.1. ASCT in frontline setting
1.1.1. Prospective studies
Among the first studies that evaluated the role of high-dose chemotherapy followed by peripheral blood progenitor cell (PBPC) autografting was the study published by Corradini et al., who pooled the results of two prospective phase II which included 62 patients with different histologies  . With a median follow-up of 76 months, the 12-year overall survival (OS) and event-free survival (EFS) rates were 34 and 30%, respectively. As expected, ALK (+) patients had an OS rate of 62% and EFS rate of 54% compared to other PTCL patients. A notable finding was also that the response status of disease prior to ASCT had prognostic significance with patients who attained complete response (CR) showing statistically significant benefit in terms of OS and EFS rates (p < 0.0001) in multivariate analysis. The intermediate-high aaIPI score was also one of the variables with predicting value of survival (10-years EFS, p < 0.02, 48% vs 25% for pts with IPI 0–1 and 2–3, respectively).
Rodriguez et al. studied 26 patients with PTCL (ALK (+) ALCL patients were excluded), who received three cycles of Mega-CHOP and an additional 4th cycle before ASCT, if the gallium scan was negative. If the gallium scan was remained positive, patients received 2 courses of IFE, and if at least partial response (PR) was achieved then they underwent ASCT  . With a median follow-up of 35 months, the estimated 3-year OS and PFS rates for all patients were 73% and 53%, respectively; while in patients, who received ASCT were 84% and 56%, respectively. After ASCT, 19 patients remained in CR. At this study, PIT and IPI system showed no prognostic value; only the chemosensitive disease after induction treatment, showed significantly impact on OS.
Mercadal et al. conducted a phase II study with 41 PTCL patients, who received 3 courses of CHOP, alternating with 3 courses of ESHAP  . Responders, who achieved at least PR, underwent ASCT. From 41 patients, 17 (41%) underwent ASCT, whereas in 17 (41%) failed the induction therapy, due to progressive disease. With a median follow-up for surviving patients of 3.2 years, the 4-year OS and progression-free survival (PFS) rates were 39% and 30%, respectively. The IPI system was the main variable for prediction of survival. However, no difference was observed in OS and PFS among the eligible patients for ASCT, regarding whether they proceeded or not.
Reimer et al. reported the results of one of the first prospective multicenter trials that evaluated the role of ASCT as upfront therapy, in 83 PTCL patients (excluding ALK (+) ALCL), where the induction regime was six cycles of CHOP  . Patients who achieved PR or CR (66% in total) proceeded to mobilization (fractionated total-body irradiation-TBI and high-dose) and ASCT. With a median follow-up time of 33 months, the estimated 3-year overall and disease-free survival (DFS) rates for patients in CR (calculated from CR to the date of relapse) and 3-year PFS rate were 48%, 53%, and 36%, respectively. These results are in consistence with results of other prospective studies with small PTCL series  .
The Nordic group conducted the largest PTCL-restricted prospective study to date, where from 166 PTCL patients, who received dose-intensified chemotherapy, 70% undergo ASCT  . In this study, ALK (+) ALCL were excluded. With a median follow-up of 60.5 months, the 5-year OS and PFS for the entire cohort was 51% and 44%, respectively.
All the published prospective studies, which have evaluated the role of ASCT in upfront setting, are summarized in Table 2 .
|Year||Author||n||High-dose regimen||Histologic subtypes||Response pro ASCT||Follow-up (months)||DFS/PFS||OS|
|2002||Gisselbrecht ||189 (84 PTCL)||ACVBP/CEOP-ECVBP
|63% CR PR1
|60||39% (5 y)||46% (5 y)|
|2004||Mounier ||28||BEAM/CBV||56% PTCL-NOS
|100% CR||78||44% (5 y)||54% (5 y)|
|2006||Corradini ||62||Mito/Mel or BEAM||45% PTCL-NOS
30% ALK + ALCL
|76||30% (12 y)||34 (12 y)|
|2007||Rodriguez ||26||BEAM||42% PTCL-NOS
31%ALK + ALCL
|35||53% (3 y)||73% (3 y)|
|2008||Mercadal ||41||BEAM/BEAC||49% PTCL-NOS
|38||30% (4 y)||39% (4 y)|
|2009||Reimer ||83||TBI-C||39% PTCL-NOS
|33||36% (3 y)||48% (3 y)|
|2009||Nickelsen ||33||Mega-CHOEP||33% PTCL-NOS
|53||26% (3 y)||45% (3 y)|
|2012||D’Amore ||166 (115 underwent ASCT)||BEAM/BEAC (at Finnish centers)||39% PTCL-NOS
4% panniculitis like
3% T/NK nasal type
31% PR (130 pts. response assessable)
|60.5||51% (5 y)||44% (5 y)|
1.1.2. Retrospective studies/randomized cooperative
A number of retrospective studies have examined the benefit of ASCT in first CR or PR of PTCL patients. However, it is expected that retrospective studies show superior survival outcome in compare to prospective studies, as only the patients who finally underwent ASCT, indicating chemosensitive disease and thus, favorable outcome, are enrolled.
The GELTAMO group analyzed 15 of 19 patients with AITL, who underwent ASCT as front-line therapy  . Most patients received peripheral stem cells coupled with BEAM or BEAC as conditioning regimen. After a median follow-up of 25 months, eight patients died (7 due to progressive disease and secondary neoplasia), while actuarial OS and PFS rates at 3 years were 60% and 55%, respectively.
Another recent attempt by Rodriguez et al. evaluated the survival benefit of ASCT after first CR. Seventy-four PTCL patients (including ALCL patients with unknown ALK status) this time were studied  . With a median follow-up time of 67 months, the 5-year OS and PFS rates were 68% and 63%, respectively. Patients with ALCL compared to patients with non-anaplastic PTCL subtypes, presented superior outcome (5-year OS 84% vs 61%, p = 0.05). Multivariate analysis showed that the patients with more than 2 risk factors of PIT prognostic system presented inferior outcome (5-year OS 31%), suggesting that ASCT may not be adequate to overcome the poor prognostic characteristics of this group.
A retrospective study conducted by Feyler et al. assessed 82 PTCL patients, including ALK (+), who proceeded to ASCT  . The 2-year OS and PFS rates for transplanted patients in first CR (48% of patients) were 64% and 61%, respectively.
In a retrospective study conducted by Prochazka et al., 29 PTCL patients were enrolled  . Among the histological subtypes were also ALCL with ALK positive, negative and unknown status, AILT lymphoma, hepatosplenic lymphoma (HSTL), Sézary syndrome and enteropathy-associated T-cell lymphoma. The median age at diagnosis was 48 years. Nineteen patients received first-line high dose therapy and ASCT consolidation (BEAM 200), while two patients of 29 were consolidated with allo-SCT with reduced-intensity conditioning (Flu-Mel-ATG) in the 1st complete remission and one patient in the 1st relapse. After a median follow-up of 55.1 months, 14 (48.3%) patients relapsed or progressed and nine patients died due to progressive disease. The 2-year EFS and OS rates were 52% and 65%, respectively.
Numata et al. administered a pre-transplant conditioning regimen (MCEC) comprising ranimustine, carboplatin, etoposide and cyclophosphamide in 32 patients, while 7 received other TBI-based regimens  . In this study the histological subtypes of AITL, ALCL with ALK unknown status, natural killer/T-cell lymphoma (NK/T) and PTCL-NOS were included. With a median follow-up of 78 months the estimated 5-year OS was 62.1%. The 5-year OS was significantly higher in patients transplanted during complete response than in those during other disease status (71.4% vs 27.3%, p = 0.046).
In a recent retrospective study conducted by Ahn et al. the effectiveness of ASCT as frontline treatment was evaluated in 31 PTCL patients  . This latest study included thirteen patients with PTCL-NOS, nine with nasal type extranodal NK/T, six with ALK (−) ALCL, two with AITL and one with HS γ-δ T-cell lymphoma. The conditioning regimen was busulfan, cyclophosphamide and etoposide (BEC). After a median follow up of 32.4 months the 3-year probability of OS and PFS was 64.5% each.
From the few randomized trials so far that evaluated the role of ASCT in PTCL, the trial LNH 93-3 was conducted on poor-prognosis aggressive lymphoma patients, including patients with T-cell immunophenotype, whereas no benefit of ASCT on OS was observed. Mounier et al. pooled the data from this trial and the GELA trial (LNH 87) and this retrospective analysis showed that B-NHL and anaplastic T-NHL exhibited the same survival, in contrast to the low survival for non-anaplastic T-NHL, while among the patients with non-anaplastic PTCL no difference in OS and PFS was observed  .
The retrospective studies of ASCT in upfront setting are summarized in Table 3 .
|Year||Author||n||High-dose regimen||Histologic subtypes||Response pro ASCT||Follow-up (months)||DFS/PFS||OS|
|2007||Rodriguez ||19||BEAM/BEAC||100% AITL||42% CR1
|25||55% (3 y)||25% (5 y)|
|2007||Rodriguez ||74||BEAM/BEAC||50% PTCL-NOS
|No data||67||63% (5 y)||67% (5 y)|
|48||50% (3 y)||53% (3 y)|
|2008||Kyriakou ||146||BEAM (74%)||100% AITL||33%CR1
|31||49% (4 y)||59% (4 y)|
|2009||Prochazka ||18||BEAM||56% PTCL-NOS
|No data||26||52% (2 y)||71% (2 y)|
|69%CR1||78||61% (5 y)||62% (5 y)|
37% ALCL (7% ALK + )
51% chemo sensitive relapse
|39||30% (4 y)||39% (4 y)|
|2011||Prochazka ||29 (19 underwent ASCT)||ProMACE-CytBOM
10% ALK + ALCL
10% ALK unknown ALCL
Enteropathy-associated T-cell lymphoma (=2)
|55.1||52% (2 y)||65% (2 y)|
|2011||Hwang ||35 (25 underwent ASCT)||BEAM
|4% Panniculitis like T-cell lym
4% γ/δ T-cell
(median prior treatment 1–4)
|39||No data||70% (3 y)|
|2013||Ahn ||31||BEC||42% PTCL-NOS
19% ALCL (−) ALK
29% extranodal NK/T (nasal)
|32.4||64.5 (3 y)||64.5 (3 y)|
14% PIF sensitive
|71||47% (3 y)||59% (3 y)|
1.2. ASCT in relapsed setting
The role of HDT and ASCT in relapse of high-grade B-NHLs has been established by many previous randomized trials such as the original PARMA phase 3 randomized controlled study, whereas the HDT–ASCT emerged as superior to second-line chemotherapy for relapsed aggressive non-Hodgkin lymphoma with diagnoses based on the Working Formulation classification  . Unfortunately, there has been no similar study in PTCLs. However, there are some retrospective studies that examine the benefit of ASCT in relapsed PTCLs, whereas there are limited data from prospective trials. All the published studies on the ASCT in relapse are listed in Table 4 .
|Year||Author||n||High-dose regimen||Histologic subtypes||Response pro ASCT||Follow-up months||DFS/PFS||OS|
Local RT CyBCNU-E
|No data||42% CR
|28||28% (2 y)||35% (2 y)|
|1999||Fanin ||64||Diverse||100% ALCL||47% CR||43||56% (5 y)||70% (5 y)|
|2001||Rodriguez ||29||BEAM/BEAC/BCE-thio/TBI-C/TBI-CE/CE/CEP||No data||38% CR
|43||32% (3 y)||39% (3 y)|
|2001||Blystad ||40||BEAM/BEAC/TBI-BEAC w/o E/TBI-C/Mel-Mito||50% PTCL-NOS
|25||56% (3 y)||58% (3 y)|
|2002||Song ||36||Mel/E||56% PTCL-NOS
|42||37% (3 y)||48% (3 y)|
|2003||Rodriguez ||115||BEAM/BEAC/TBI-C/CVB/others||63% PTCL-NOS
|37||60% (5 y)
49% (5 y) at 2 line
|56% (5 y)
45% (5 y) at 2 line
|2003||Schetelig ||29||BEAM, BEAM-like/ICE, ICE-like/TBI-C/BC/others||100% AITL||No data||60||37% (5 y)
39% (5 y) at 2 line
|60% (5 y)
44% (5 y) at 2 line
|2004||Zamkoff ||16||TBI-C/Thio-CE/CE-Carm/BC/TBI-CE||100% ALCL ALK (−)||60% CR
|No data||12 weeks||72 weeks|
|2004||Jantunen ||37||BEAC/BEAM||38% PTCL-NOS
|87% CR/PR||24||44% (5 y)
28% (5 y) at 2 line
|54% (5 y)
45% (5 y) at 2 line
|2004||Jagasia ||28||TBI-CE/CVB||21% PTCL-NOS
|44||50 (3 y)||69% (3 y)|
|2006||Kewalramani ||24||TBI/chemo alone (no data)||58% PTCL-NOS
|72||24% (5 y)||33% (5 y)|
|2007||Kim ||40||BEAM/BEAC/BEC/CE||50% PTCL-NOS
|16||No data||11.5 months|
|2007||Smith ||32||BEC||34% PTCL-NOS
|No data||30||18% (5 y)||34% (5 y)|
|2007||Feyer ||64 (ASCT)
28% T-cell leukemia/lymphoma
6% cutaneous TCL
|37||50% (3 y)
49% (2 y) CR2/PR/SD
37% (2 y) PD
|53% (3 y)
49% (2 y) CR2/PR/SD
34% (2 y) PD
|89% CR/PR||60||25% (5 y)
9% (5 y) at 2 line
|48% (5 y)
37% (5 y) at 2 line
|2008||Lee ||47||CVB/MCEC/BEAM||100% NK/T||58% CR||117||No data||No data|
|2009||Yang ||64||BEAM/CVB||100% PTCL-NOS||33% CR
|30||44% (3 y)
33% (3 y) at 2 line
|53% (3 y)
46% (3 y) at 2 line
|2011||Mak ||38 (21 ASCT/17 allo-SCT)||No data||No data (ALCL + ALK incl.)||No data||∼48||48% (3 y)||55% (3 y)|
|2011||Nademanee ||67||Pts < 60 TBI + E/C
pts≥60 BCNU or BEAM
|21% CR1/PR1||65.8||75% 5 y||54%|
11% ALK (−)
6% ALK (+)
14 ALK unknown
In 2001, thirty-six PTCL patients, who experienced disease recurrence after conventional chemotherapy, with relapsed or refractory disease and proceeded to ASCT (n = 29) and allo-SCT (n = 7), were analyzed retrospectively by Rodriguez et al.  . The median number of prior regimens was 3 (range 1–4). It was shown that with a median follow-up period of 43 months, the 3-year OS and PFS rates were 36% and 28%, respectively.
In the same year, Blystad et al. analyzed 40 PTCL patients (including ALK with unknown status) with median age of 41.5 years, who received as conditioning regimens BEAM, BEAC, cyclophosphamide and total body irradiation (TBI), BEAC without etoposide and TBI, and mitoxantrone in combination with melphalan  . The estimated OS at 3 years was 58%, the EFS 48% and the relapse-free survival (RFS) 56%, with a median follow-up of 36 months (range 7–100) for surviving patients; with patients, not surprisingly, with ALCL to have a better prognosis compared to those with other PTCL subtypes (OS 79% vs 44%, respectively). Twenty-three patients were transplanted in CR2/CR3 (n = 17) or PR2 (n = 6).
Also, Song et al. analyzed retrospectively 36 patients with primary refractory or relapsed chemosensitive disease, who received high-dose melphalan and etoposide with or without TBI supported by unpurged autologous stem cells and the comparisons were made with 97 diffuse large B-cell lymphoma (DLBL) patients  . With a median follow-up period of 42 months the estimated 3-year OS and EFS rates were 48% and 37%, respectively for PTCLs, in comparison to rates of patients with DLBL 53% and 42%, respectively. There was no significant prognostic variable found by univariate analysis for the PTCL cohort. The 20 PTCL-NOS patients exhibited an inferior EFS compared with DLBL patients (23%, p = 0.028).
The GEL-TAMO group reported a survival benefit for PTCL patients who underwent ASCT in first CR (CR1)  . One hundred fifteen patients with median age 41 years were evaluated (including 7% ALCL patients with unknown ALK status). From the patients who transplanted 86% attained a CR and 5% PR. With a median follow-up time of 37 months, the estimated 5-year OS, TTF and DFS rates were 56%, 51% and 60%, respectively; while for the 37 patients transplanted in CR1, the 5-year OS and DFS rates were 80% and 79%, respectively, though these results must be interpreted carefully due to young median age and the unknown status of ALK of enrolled patients. At the same study also, the lactase dehydrogenase (LDH) serum levels, a-IPI and disease status pre-transplant were associated with outcome.
Zamkoff et al. evaluated the effect of ASCT on ALCL ALK (−) patients’ outcome, a specific PTCL subtype that is associated with extremely poor prognosis  . In 16 patients with a median age 51 years, who underwent ASCT at the time of first relapse, the median OS and PFS were 72 and 12 weeks, respectively (15 patients, as 1 patient was lost of follow-up), indicating that probably ASCT neither offers a survival benefit nor prolongs the DFS in patients with recurrent chemotherapy-sensitive ALCL ALK (−).
A nationwide survey of Jantunen et al. evaluated 37 PTCL patients in Finland with median age of 46 years after histopathology review, which included PTCL-NOS, ALCLs and other subtypes  . With a median follow-up time of 24 months from HDT, 16 patients (43%) have relapsed or progressed. The estimated 5-year OS was 54%. Patients with ALCL had superior OS when compared with other subtypes (85 vs 35%, p = 0.007). For patients who proceeded to ASCT in CR/PR status the 5-year OS rate was 63% compared to patients transplanted in other disease status (45%, though these results did not reach statistical significance).
Feyler et al. reported the results of a retrospective study of 82 PTCL patients (including ALK (+) and ALK (−)) who received HDT and proceeded to ASCT (n = 64) and allo-SCT (n = 18)  . With a median follow-up from ASCT of 37 months from transplant, for 20 out of 82 patients, who transplanted as consolidation therapy for relapsed disease (CR2/PR/SD), the 2-year OS and PFS were 49% each; while the 2-year OS and PFS for those transplanted with refractory disease (n = 13) were 34 and 37%, respectively. In the multivariate analysis, the only factor with significant impact was chemotherapy sensitivity.
The Korean group investigated the prognostic factors for ASCT in 64 PTCL-NOS patients. Thirty-six patients received 2 or more chemotherapy regimens (CHOP-based) before transplantation  . The 3-year OS and PFS rates were 53% and 44.3%, respectively. However, 5 patients were transplanted in CR2 and 25 in PR2 after salvage chemotherapy, while 6 patients underwent HDT–ASCT in progressive or chemorefractory disease. The 3-year OS rate for patients in CR2 was 70.9%, compared with 50% for those in PR1. The patients who underwent ASCT as salvage treatment presented 3-year OS 37.7%. It was demonstrated that ASCT offers little benefit in patients with high aaIPI or PIT.
In a recent study conducted by Czyz et al. sixty-five PTCL patients who underwent ASCT as a consolidation of first response achieved with induction or salvage chemotherapy, were analyzed retrospectively  . Twelve patients received second-line chemotherapy as a salvage therapy after primary induction failure, and proceeded to ASCT. With a median follow up period of 53 months, the 5-year OS for all patients was 61.5%, whereas for patients with primary induction failure was 41%.
1.3. Allo-SCT in PTCL
Despite the limitations of retrospective analyses, the small series of patients, the variety of subtypes of PTCL (including all subtypes, in some cases with unknown histological features) and the conditioning regimens (myeloablative, reduced intensity), the role of allo-SCT has been investigated especially in relapsed and/or refractory PTCL.
In a phase II Corradini et al. evaluated the outcome of 17 patients with relapsed or refractory PTCL (refractory to chemotherapy n = 2, relapsed disease n = 15, and 8 patients of them relapsed after ASCT), who received reduced intensity allo-SCT  . With a median follow-up period of 28 months, the estimated 3-year OS and PFS were 81% and 64%, respectively. Donor lymphocyte infusions induced a response in two patients with progressive disease, suggesting the existence of a graft-versus-lymphoma effect (GVL).
Feyler et al. in the conducted retrospective study of 82 patients with PTCL, included 18 patients with relapsed and/or refractory PTCL, who underwent allo-SCT  . With a median follow-up time of 57 months, the estimated 3-year OS, PFS and relapse rates were 39%, 33% and 28%, respectively.
Kyriakou et al. conducted a retrospective study from the EBMT, including 45 patients with AITL who underwent allo-SCT  . The estimated 3-year OS, PFS and relapse rates were 64%, 53% and 20% (lower in patients who developed GVHD), respectively.
In a recent retrospective study, Kanakry et al. reviewed the outcomes of 44 related donor allogeneic blood or marrow transplantation for PTCL, with 24 patients who received reduced-intensity conditioning (RIC) and 20 patients who received myeloablative conditioning (MAC). The estimated 2-year PFS and OS rates were 40% and 43%, respectively  .
All the studies which evaluated the Allo-SCT in PTCL are listed in Table 5 .
|Year||Author||n||High-dose regimen||Histologic subtypes||Response pro SCT||Follow-up (months)||TRM||DFS/PFS||OS|
|Per conditioning regime|
|2004||Corradini ||17||100% RIC||53% PTCL-NOS
23.5% ALCL-ALK (−)
|28||RIC(2 y):6%||64% (3 y)||81% (3 y)|
|2005||Murashige ||28||82% MAC
11% Blastic NK
|57% CR||34||RIC(1 y):20%
|34% (2 y)||40% (2 y)
|2007||Feyler ||18||100% MAC||50% PTCL-NOS
28% T-cell leukemia
|No data||57||MAC(3 y):39%||33% (3 y)||39% (3 y)|
|2008||Hamadani ||14||57% MAC
|34||(Overall) 57% (3 y)
|31% (3 y)||35% (3 y)
|2008||Le Gouill ||77||74% MAC
|43||(overall) 34% (5 y)
Non-significance MIC vs RIC
|53% (5 y)||57% (5 y)
Non-significance MIC vs RIC
|2009||Kyriakou ||45||56% MAC
|100% AITL||27% CR
|53% (3 y)||64% (3 y)
|2012||Dodero ||52||100% Thio-RIC||45% PTCL-NOS
||RIC(5 y):12%||40% (5 y)||50% (5 y)|
|2013||Kanakry ||44||55% RIC
11% ATCL ALK (−)
4% ATCL ALK(+)
7% ATCL unknown ALK
|32% PR/CR w/o PIF 25% active disease
|40% (2 y)||43% (2 y)
|2013||Smith ||126||MAC 59%
18% PIF sensitive
In conclusion, allo-SCT may offer a benefit in a subgroup of PTCL patients, with relapsed after ASCT disease. Patients with a matched related or unrelated donor, a good performance status could be eligible for allo-SCT.
PTCLs have been the “poor step-child” of lymphomas, regarding the inferior prognosis in compare to their B-cell counterparts. It is essential to treat the aggressive PTCLs quite differently than aggressive B-cell lymphomas as they constitute a distinct disease entity with different biological features, which probably are responsible for the dramatic difference in response to various therapies. To date, the regimens that are used in the PTCL treatment may induce high remissions rates; however, durable remissions are rare.
With regard to ASCT in first complete remission, retrospective analyses suggest possible benefit, although the published data present limitations, due to retrospective character of studies, the heterogeneity of conditioning regimens, the small series of patients and the variety of subtypes; no safe conclusion can be drawn. Despite the lack of randomized PTCL-restricted trials, the consolidation of CR1 with ASCT could be feasible and safe. However, the high relapse rates, resulting in ineligibility for ASCT, indicate the need of new more effective induction chemoregimens that to date is under investigation. Praletrexate, a folate analog metabolic inhibitor and the first drug to gain FDA approval for the treatment of relapsed or refractrory PTCL could be also a potent agent alone or in combination for induction treatment  and .
Bendamustine that showed efficacy in relapsed or refractory PTCL with ORR of 50% and median OS of 6.2 months may improve response rates as part of an induction therapeutic strategy  .
Bortezomib, a proteasome inhibitor that already used in treatment of multiple myeloma and mantle cell lymphoma has shown very promising results in combination with CHOP in frontline therapy of advanced stage PTCL  and .
A phase II study of lenalidomide that conducted in 24 relapsed PTCL patients, showed ORR of 30% and PFS of 95 days  . There are a number of HDAC inhibitors being studied in PTCL including vorinostat, panobinostat, romidepsin and belinostat. Vorinostat and romidepsin have shown single-agent activity in CTCL that resulted in FDA approval of vorinostat in 2006 for the treatment of advanced and refractory CTCL  and in 2009 of romidepsin for the same indication, based on a demonstrated ORR of 34% in 2 clinical trials , , and . Gemcitabine is the most effective pyrimidine nucleoside analog in PTCL treatment, showing activity both as a single agent , , and  and in combination with alemtuzumab  and bortezomib  and . In a recent study conducted by Southwest Oncology Group, the combination of gemcitabine with cisplatin, etoposide and methylprednisolone was evaluated in 33 newly diagnosed PTCL patients  . The 2-year PFS rate was 12% and the median PFS was 7 months, whereas the 2-year OS rate was 31% and the median OS was 17 months.
Moreover, several monoclonal antibodies are currently being tested in PTCL therapy including anti-CD30 antibodies (SFN-30, blenduximab vetodin, iratumumab), anti-CD52 antibodies such as alemtuzumab and siplizumab, an anti-CD2 antibody , , and . In 2011 the CD30 targeting antibody-drug conjugate brentuximab vedotin (SGN-35) was approved by the FDA for the treatment of relapsed Hodgkin lymphoma and ALCL based on the impressive results of two pivotal phase II trials , , and . Alemtuzumab, a CD52 humanized monoclonal antibody has been shown to be an effective alternative option for patients with PTCL and CTCL. In combination with CHOP, CHOEP or DHAP, alemtuzumab showed encouraging results with respect to efficacy in patients with relapsed or refractory PTCL, although the toxicity of these regimens was considerable with the life-threatening CMV infection being the main adverse event , , and . We are eagerly waiting the final results of the ongoing trial that evaluates the efficacy of alemtuzumab in combination with CHOP in young PTCL previously untreated patients  .
However, the antracycline-based regimens remain the most administered therapeutic options in frontline therapy of all PTCL except from NK/T lymphoma, nasal type, so building on CHOP/CHOEP backbone could form more effective therapeutic strategies.
To summarize, in the majority of studies of ASCT in PTCL improved OS and PFS rates are shown in compare to chemotherapy alone. However, there is an urgent need of prospective randomized trials; some of them are ongoing in order to unveil the difference between conventional chemotherapy and HDT–ASCT. While this question remains to be answered, it has been already demonstrated that the response status of disease prior to transplantation, the performance status of patients and the PIT score (in some studies) affect the outcome.
On the basis of published experience, the ASCT seems to be an effective approach in the salvage setting for treatment of PTCL patients, showing similar results in comparison to aggressive diffuse large B-cell lymphomas. For PTCL patients with chemosensitive disease and in good performance status, ASCT as part of salvage therapy could be an adequate treatment, showing 3-year OS from 39% to 69%.
Allo-SCT under specific circumstances could offer a curative choice for relapse and/or refractory disease and prior ASCT failure. Patients in young age, in good performance status and with a leukocyte antigen-compatible related or unrelated donor should be considered as eligible. In most of the studies GVL effect has been arisen. Additionally, there are no adequate data that could recommend the administration of reduced-intensity or myeloablative conditioning regime.
In conclusion, prospective studies investigating the role of ASCT and allo-SCT in PTCL patients, though the difficulty of rarity of disease, the variety of subtypes and their outcomes should be conducted. The poor outcome of PTCL patients and the low response rates to currently administered regimens warrant the urgent need for investigation of novel agents and development of more effective therapeutic strategies. Therefore, in the absence of recommended treatment of such an aggressive disease, PTCL patients should be encouraged to participate in clinical trials.
Dr. Won Seog Kim, Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medecine, 81 Irwon-ro Gangnam-gu, Deoul 135-710, Republic of Korea.
Michael J. Robertson, M.D., Indiana University School of Medicine, Department of Medicine, Division of Hematology/Oncology, Indiana Cancer Pavilion, Room 473, 535 Barnhill Drive, Indianapolis, IN 46202-5289, United States.
Professor A.M. Beitinjaneh, Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, United States.
The authors gratefully acknowledge Dr. Evangelos Terpos in drafting and editing the manuscript.
M.G. designed the study, analyzed the data and prepared the manuscript. C.P. designed the study and edited the manuscript.
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Dr. Maria Gkotzamanidou obtained her M.D. from Medical School, University of Athens in Greece in 2008. In 2012 she earned her Ph.D. degree in Medical oncology from University of Athens under the supervision of Prof. Athanasios – Meletios Dimopoulos. She is currently a Research Fellow in Medical Oncology Department in Dana-Farber Cancer Institute, Harvard Medical School in Boston.
Dr. Christos A. Papadimitriou is an Associate Professor of Medicine at Department of Clinical Therapeutics in Medical School, University of Athens. He is the director of the autologous stem cell transplantation unit in Alexandra Hospital in Athens, Greece. He has authored or co-authored over 90 peer-reviewed articles and reviews. His current research interests include: Transplantation in hematologic malignancies and solid tumors, breast cancer and multiple myeloma.
a Department of Medical Oncology Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
b VA Boston Healthcare System, Harvard Medical School, Boston, MA 02115, USA
c Department of Clinical Therapeutics, Alexandra Hospital, Medical School-University of Athens, Greece
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