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Review

Recent advances in understanding and managing T-cell lymphoma

[version 1; peer review: 2 approved]
Jun Ho Yi
https://orcid.org/0000-0003-1499-7131
1, Seok Jin Kim2, Won Seog Kim2
Jun Ho Yi
https://orcid.org/0000-0003-1499-7131
1, Seok Jin Kim2, Won Seog Kim2
PUBLISHED 12 Dec 2017
Author details Author details
OPEN PEER REVIEW
REVIEWER STATUS

Abstract

Owing to the rarity of peripheral T-cell lymphoma (PTCL) and the heterogeneity of subtypes, there are no compelling data to guide the therapeutic approaches for such patients. Over the years, there have been remarkable advances in molecular subtyping and treatment of PTCL, although there are still many areas to be explored. In this review, we summarize recent updates on the evolution of understanding and treatment for PTCL.

Keywords

T-Cell lymphoma, PTCL, T-lymphocytes, Natural Killer Cells

Corresponding author: Won Seog Kim
Competing interests: No competing interests were disclosed.
Grant information: The author(s) declared that no grants were involved in supporting this work.
Copyright:  © 2017 Yi JH et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
How to cite: Yi JH, Kim SJ and Kim WS. Recent advances in understanding and managing T-cell lymphoma [version 1; peer review: 2 approved]. F1000Research 2017, 6(F1000 Faculty Rev):2123 (https://doi.org/10.12688/f1000research.12573.1) First published: 12 Dec 2017, 6(F1000 Faculty Rev):2123 (https://doi.org/10.12688/f1000research.12573.1) Latest published: 12 Dec 2017, 6(F1000 Faculty Rev):2123 (https://doi.org/10.12688/f1000research.12573.1)

Introduction

T/natural killer (T/NK) cell lymphoma represents a heterogeneous group of malignant lymphoproliferative diseases that arise from T-lymphocytes and NK cells. To distinguish it from immature T-cell neoplasms such as lymphoblastic leukemia/lymphoma, mature T-cell lymphoma is often called peripheral T-cell lymphoma (PTCL). PTCL accounts for approximately 15% of all non-Hodgkin’s lymphoma cases worldwide and shows regional differences in distribution.

Over the years, the molecular understanding of PTCL has advanced remarkably; as a result, the classification of PTCL was recently revised1. In addition, with new combinations of older drugs, novel agents such as checkpoint inhibitors, epigenetic modulators, and anti-folates have been introduced for the treatment of PTCL. Despite this progress, the prognosis for PTCL is worse than that for B-cell lymphoma, even than that before the era of rituximab2,3.

In this concise review, we provide an overview of the latest advances in the management of PTCL focusing on trials that have been carried out with novel agents. Of note, this review does not cover cutaneous T-cell lymphoma (CTCL) or extranodal NK-T cell lymphoma (ENKTL), because their biological features and treatment strategies differ from those of PTCL.

Brief review of the 2016 World Health Organization revision of nodal/extranodal peripheral T-cell lymphomas

Beginning with nodal PTCLs, up to 60–100% of angioimmunoblastic T-cell lymphoma (AITL) and up to 40% of PTCL not otherwise specified (PTCL-NOS) demonstrate surface markers of follicular helper T (TFH) cells4–7 and have common genetic features, such as RHOA, TET2, DNMT3A, and IDH8–11. Two provisional entities have been introduced: follicular T-cell lymphoma and nodal peripheral T-cell lymphoma with the TFH phenotype. These entities can be diagnosed when their neoplastic cells express at least two or three TFH markers but do not display the clinicopathologic features of AITL, which would have been diagnosed as PTCL-NOS according to the 2008 World Health Organization classification. AITL and these two new entities are now categorized as nodal T-cell lymphoma with the TFH phenotype.

By definition, the PTCL-NOS designation encompasses all PTCLs lacking specific features that would allow categorization within any of the better-defined subtypes of PTCL, resulting in heterogeneity of this entity. A recent gene expression profiling study demonstrated that PTCL-NOS can be classified into two molecular groups according to the overexpression of either GATA3 or TBX2112, and the GATA3 subset shows inferior outcomes. However, as this study has not been applied in routine practice, the results have not led to the description of new entities.

ALK-negative anaplastic large-cell lymphoma (ALCL), which was a provisional entity in the 2008 classifications, has become a definite entity. This CD30-expressing neoplasm is not distinguishable from its ALK-positive counterpart on morphologic grounds, except for the absence of ALK expression. While the prognosis of ALK-negative ALCL is known to be less favorable13, the five-year survival rate is comparable to that of ALK-positive ALC when DUSP22 rearrangements are found14. After first being described in 199715, breast implant-associated ALCL emerged as a distinct clinicopathologic entity, and it was proposed as a new entity in the 2016 classifications. All reported cases are ALK-negative, and the tumor is more frequently confined to the fibrous capsule. These cases show indolent clinical courses and respond well to implant removal and resection of the tumor. However, when the tumor presents with a mass discernible by radiologic or gross pathologic examination, it might be associated with a more aggressive clinical course16,17.

Major changes in extranodal PTCL cases have emerged from diseases that occur in the gastrointestinal (GI) tract. Enteropathy-associated T-cell lymphoma (EATL) is composed of two subtypes; type I EATL usually occurs following long-standing celiac disease (CD), showing large pleomorphic cells within an inflammatory background, and type II EATL occurs without antecedent CD, showing small, monotonous cells with epitheliotropism. In the 2016 classifications, diagnosis of EATL is to be used only for what was formerly type I EATL. Type II EATL has changed its name to monomorphic epitheliotropic intestinal T-cell lymphoma; it has been proposed as a new entity on the basis of its histologic, genetic, and molecular differences18–20. Whereas these two highly aggressive diseases show transmural growth, which often leads to GI bleeding or perforation, there is another one that grows superficially along the GI mucosa. Indolent T-cell lymphoproliferative disorder of the GI tract is a new provisional entity that usually presents with chronic diarrhea, weight loss, and malnutrition, mimicking the symptoms of inflammatory bowel disease21. The course of this disease is known to be indolent, although some cases of transformation have been reported22.

Current standard of care: conventional chemotherapy

Anthracycline-containing regimens such as a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP plus etoposide (CHOEP) are recommended as the front-line treatments for PTCLs23,24. Although clinical outcomes for these regimens vary according to histologic subtype, complete response (CR) rates range from 30% to 70%, and five-year overall survival (OS) rates range from 20% to 60%. Except in several small subsets, such as patients with ALK-positive ALCL or those with a low international prognostic index, the use of anthracycline-containing regimens failed to improve clinical outcomes25–27. Owing to the lack of efficacy of conventional CHOP, more intensive anthracycline-based regimens have been tried28–32; however, given limitations of small numbers of patients, intractable toxicities, and unfavorable results, none is considered a standard option. CHOP-14 or CHOEP can still be considered in select patients33,34.

Various combinations of several non-anthracycline drugs have been evaluated in front-line settings. In the S0350 trial, a combination of cisplatin, etoposide, gemcitabine, and solu-medrol (PEGS) was tried in 26 patients with newly diagnosed PTCL35. The two-year progression-free survival (PFS) rate was 14%, and the two-year OS rate was 36%, which seemed to be no better than those of conventional combinations. Gemcitabine and etoposide were added to CHOP in 26 patients with newly diagnosed PTCL and this resulted in a CR rate of 62% and a median 215 days of event-free survival36. An Italian group reported outcomes of biweekly administration of six cycles of gemcitabine, ifosfamide, and oxaliplatin in 21 patients with high-risk PTCL. The CR rate was 67%, and the five-year event-free survival rate was 49%. In a recent report from the randomized phase II study of the UK group using the combination of gemcitabine, cisplatin, and methylprednisolone (GEM-P), objective response rates (ORRs) were 57.1% for the CHOP arm and 43.2% for the experimental arm37. Although grade 3–4 neutropenia or febrile neutropenia was more common in the CHOP arm, there was no difference in the two-year OS rate (53.1% versus 64.7%) or PFS rate (36.0% versus 39.0%). Outcomes of the recent trials for front-line treatment are summarized in Table 1.

Table 1. Summary of the recent trials of front-line treatment for peripheral T-cell lymphoma.

RegimensPhaseTotal
accrual		CR/PR
rates		Survival
outcomes		Grade 3–4 toxicities
CHOP-based combinations
Everolimus + CHOP123II3057%/33%2-year PFS: 33%
2-year OS: 70%		Neutropenia: 80%
Thrombocytopenia: 60%
Bortezomib + CHOP114II4665%/9%2-year PFS: 37%
2-year OS: 52%		Neutropenia: 41%
Romidepsin + CHOP65Ib/II3751%/17%30-months PFS: 41%
30-months OS: 71%		Neutropenia: 89%
Thrombocytopenia: 78%
Belinostat + CHOP100Ib2372%/17%Not reportedNeutropenia: 26%
Anemia: 22%
Non-anthracycline combinations
Cyclophosphamide, etoposide, vincristine,
prednisone alternating with pralatrexate80		II3352%/18%2-year PFS: 39%
2-year OS: 60%
Gemcitabine, etoposide, cisplatin,
methylprednisolone35		II2623%/15%2-year PFS: 14%
2-year OS: 36%		Neutropenia: 45%
Anemia: 24%
Gemcitabine, cisplatin,
methylprednisolone37		II4443%/not
reported		2-year PFS: 39%
2-year OS: 65%
Gemcitabine, cisplatin, prednisone,
thalidomide111		II5252%/15%2-year PFS: 57%
2-year OS: 71%		Myelosuppression: 44%

CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CR, complete response; OS, overall survival; PFS, progression-free survival; PR, partial response.

Collectively, although there is limited evidence that CHOP or its variants improve the prognosis of patients with PTCL, there is also little evidence that a certain non-anthracycline combination can replace CHOP. A randomized phase II study is under way to compare a combination of ifosfamide, carboplatin, and etoposide (ICE) and dexamethasone with CHOP (NCT02445404).

Current standard of care: consolidation therapy

Except for ALK-positive ALCLs, which show favorable outcomes with chemotherapy alone, current guidelines recommend consolidative autologous stem cell transplantation (ASCT) in patients with chemosensitive PTCL23,24. However, this recommendation was not established based on prospective randomized trials.

In a report by Reimer et al., 83 patients with PTCL received four to six cycles of CHOP, and for patients in partial response (PR) or CR at the end of induction, ASCT was performed38. Fifty-five patients advanced to ASCT, and the three-year OS for patients who underwent ASCT was 71%. In the NLG-T-01 trial, 115 out of 160 patients with PTCL underwent ASCT after induction treatment of CHOEP-14 or CHOP-1439. The 5-year PFS and OS rates were 44% and 51%, respectively, and the recently announced follow-up data revealed that the 10-year PFS and OS rates were 38% and 41%, respectively40. Although it appears that prolonged survival can be achieved by ASCT, it should be noted that approximately 30% of patients are unable to receive it and this is mostly due to early progression. Several studies have compared the efficacy of front-line allogeneic stem cell transplantation (alloSCT) with ASCT41,42; however, the outcomes of alloSCT were not significantly different from those of ASCT. Taken together, these data suggest that ASCT should be considered as the first treatment in patients with chemosensitive PTCL.

Current standard of care: relapsed or refractory peripheral T-cell lymphoma

Up to 20–30% of patients fail to achieve an initial response, and even after ASCT, over 50% will experience relapsed disease38,39. For those who have relapsed or refractory PTCL (rrPTCL), salvage chemotherapy with or without subsequent consolidation treatment can produce long-term remission. However, owing to refractoriness of the disease, overall outcomes remain poor43. Several novel agents are actively being investigated in patients with rrPTCL. The major clinical findings of the studies with novel agents are summarized in Table 2.

Table 2. Selected studies of novel agents in the treatment of relapsed/refractory peripheral T-cell lymphomas.

AgentPhaseTotal
accrual		CR/PR
rates		Survival outcomesMajor grade 3–4 toxicities
Monoclonal antibodies
Brentuximab vedotinII5258 (ALCL)57%/29%1-year OS rate: 70%
4-year OS rate: 64%
5-year OS rate: 60%		Peripheral sensory neuropathy,
neutropenia, thrombocytopenia
II5835
(non-ALCL)		24%/18%Median PFS: 2.6 monthsPeripheral sensory neuropathy,
neutropenia, hyperkalemia
MogamulizumabII643814%/19%Median PFS: 3.0 monthsLymphocytopenia, neutropenia
Anti-folates
PralatrexateII7611111%/18%Median PFS: 3.5 months
Median OS: 14.5 months		Neutropenia, thrombocytopenia,
mucositis
Histone deacetylase inhibitors
RomidepsinII8913115%/11%Median PFS: 4.0 months
Median OS: 11.3 months		Neutropenia, thrombocytopenia
Romidepsin + gemcitabineII942015%/15%2-year PFS: 11%
2-year OS: 50%		Neutropenia, thrombocytopenia,
anemia
BelinostatII9812011%/15%Median PFS: 1.6 months
Median OS: 7.9 months		Neutropenia, fatigue
ChidamideII1028314%/15%Median PFS: 2.1 months
Median OS: 21.4 months		Neutropenia, thrombocytopenia
Immunomodulatory drugs
LenalidomideII1085411%/11%Median PFS: 1.9 monthsNeutropenia, thrombocytopenia,
pneumonia, gastrointestinal disorder
II109408%/18%Median PFS: 4 months
Median OS: 12 months		Neutropenia, pain, dyspnea
Inhibitors of PI3K/mTOR pathways
DuvelisibI1171513%/33%Median OS: 36.4 weeksHepatitis, rash, neutropenia
CopanlisibII1191714%/7%Not reportedHypertension, neutropenia,
hyperglycemia
EverolimusII124166%/38%Median PFS: 4.1 months
Median OS: 10.2 months		Neutropenia, thrombocytopenia,
anemia, hyperglycemia
Alternative agents
BendamustineII1256028%/22%Median PFS: 3.6 months
Median OS: 6.2 months		Neutropenia, thrombocytopenia,
infection
Bendamustine + carboplatin
+ dexamethasone		II1263030%/25%Median PFS: 4.8 monthsNeutropenia, thrombocytopenia,
anemia
AlisertibIII13012016%/17%Median PFS: 3.7 months
Median OS: 9.9 months		Neutropenia, thrombocytopenia,
anemia
TipifarnibII132180%/17%Not reportedNeutropenia, thrombocytopenia

ALCL, anaplastic large-cell lymphoma; CR, complete response; OS, overall survival; PFS, progression-free survival; PR, partial response.

Monoclonal antibodies

Alemtuzumab

Alemtuzumab is a humanized monoclonal antibody (mAb) against CD52. As a salvage treatment, it has been evaluated either as monotherapy44 or as combination therapy with various backbones45–47. Although high CR rates were observed (36–54%), severe opportunistic infections caused concerns. Combinations of alemtuzumab with conventional three-weekly CHOP48, two-weekly CHOP49, four-weekly CHOP50, and CHOEP-1451 have been assessed in patients with newly diagnosed PTCL. Again, high CR rates (59–71%) were accompanied by profound hematologic toxicity and opportunistic infection. Two international phase III trials are ongoing to evaluate the role of alemtuzumab when added to the first four (out of six) cycles of CHOP-14 (NCT00646854 and NCT00725231).

Brentuximab vedotin

Brentuximab vedotin (BV) is an antibody-drug conjugate comprising an anti-CD30 mAb conjugated to an anti-microtubule agent, monomethyl auristatin E. As CD30 is typically expressed in Hodgkin’s lymphoma and ALCL, most major findings have been achieved in those diseases. In a pivotal phase II trial, patients with relapsed or refractory systemic ALCL received BV 1.8 mg/kg every three weeks for up to 16 cycles52. Among 58 patients, the ORR was 86% (n = 50) and 33 patients (57%) achieved CR. The four- and five-year survival data demonstrated that long-term remission can be achieved by BV treatment53,54. For PTCLs other than ALCL, the rate of CD30 positivity varies according to subtype and report14,55–57. During a phase II trial in which 35 patients with relapsed or refractory CD30-positive PTCL (22 PTCL-NOS and 13 AITL) received BV at a dose of 1.8 mg/kg every three weeks, the ORR was 41% (95% confidence interval 24.6–59.3), and the PFS of patients with AITL was longer than that of the patients with PTCL-NOS (6.7 versus 1.6 months)58. Several BV-based combinations have also been evaluated. In a phase I trial, 39 treatment-naïve patients with a diagnosis of CD30-positive PTCL were recruited to receive either sequential treatment (two cycles of BV, six cycles of CHOP, and eight cycles of BV) or combination treatment (six cycles of BV in combination with vincristine-omitted CHP and 10 cycles of BV)59. There were seven patients with non-ALCL PTCL—two PTCL-NOS, two AITL, two adult T-cell leukemia/lymphoma (ATLL), and one EATL—they were all allocated to a combination arm for which a CR rate of 100% was noted. A subsequent four-year follow-up analysis revealed that six out of seven of them were still alive60. Based on these favorable outcomes, a randomized phase III trial is ongoing to compare BV-CHP versus CHOP in patients with CD30-positive PTCL (ECHELON-2 (A Comparison of Brentuximab Vedotin and CHP With Standard-of-care CHOP in the Treatment of Patients With CD30-positive Mature T-cell Lymphomas)) trial, NCT01777152).

Mogamulizumab

Mogamulizumab is a humanized mAb targeting the CC chemokine receptor 4 (CCR4), which is expressed in physiologic regulatory T cells. CCR4 is also expressed in nearly 90% of ATLL cases61 and in approximately 30–65% of patients with PTCLs62,63, and expression of CCR4 is associated with poor survival. In a Japanese phase II trial, 29 patients with CCR4-positive, relapsed PTCL were recruited to receive mogamulizumab at a dose of 1.0 mg/kg per week for eight weeks64. Five CRs and PRs, which made up 34% of the ORR, were noted. Lymphopenia was the most frequent adverse event (grade 3–4, 73%), and 51% of patients experienced skin disorders of any grade. The degree of CCR4 expression was not correlated with the clinical response. However, in a European phase II trial, a lower ORR was noted65. Of 35 patients with rrPTCL, only one CR and three PRs were noted, and the ORR was 11.4%. The lower ORR can be explained by the different setting (relapsed only versus relapsed or refractory patients), the poorer performance status of the European study population (0% versus 40% of patients were Eastern Cooperative Oncology Group performance status 2), or the lower dose intensity of the administration schedule (weekly administration for eight weeks versus weekly administration for four weeks followed by biweekly administration).

Immune checkpoint inhibitors

It has long been recognized that the tumor microenvironment plays important roles in lymphomagenesis, proliferation, and immune evasion66,67. In T-cell lymphoma, the microenvironment defines the tumor itself (such as in AITL), and many subtypes manifest strong tissue tropism (such as in CTCL or primary GI lymphomas).

Given that PD-1 is expressed in a substantial portion of PTCL cases68 and that PD-L1 is frequently expressed in certain virus-associated lymphomas69, this pathway is of major interest. Nivolumab is a fully human anti-PD1 mAb. In a phase I, dose-escalating study, a total of 81 patients with lymphoid malignancy (B-cell lymphoma 31, T-cell lymphoma 23, and multiple myeloma 27) received nivolumab at doses of 1 or 3 mg/kg every two weeks70. Among five patients with PTCL, two PRs were observed, and the median PFS was 14 weeks. In the two responding patients with PTCL, a sustained duration of response (DoR) was observed. Several trials are ongoing to evaluate the role of this agent in patients with PTCL as a monotherapy (NCT03075553 and NCT02973113) or as combination therapy with BV (NCT0258163). Evaluation of pembrolizumab, another PD-1 mAb, in PTCL has been based on anecdote71,72, and two studies are under way for patients with rrPTCL (NCT03021057 and NCT02362997). In regard to mAbs targeting PD-L1 or PD-L2 or both, prospective studies with avelumab (NCT03046953) and durvalumab (NCT03161223 and NCT03011814) are taking place.

Ipilimumab is a fully humanized mAb targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4). In a phase I study, nivolumab combined with ipilimumab was given at 3 mg/kg or 1 mg/kg every three weeks for four doses, and this was followed by nivolumab monotherapy every two weeks73. Eleven patients with heavily pre-treated T-cell lymphoma were included, one PR and four standard deviations were noted, and one patient proceeded to alloSCT.

Anti-folates

Anti-folates demonstrate anti-tumor efficacy by inhibiting dihydrofolate reductase, which converts dihydrofolate to tetrahydrofolate. Depletion of tetrahydrofolate disrupts the synthesis of pyrimidines and amino acids such as serine, glycine, and methionine74.

Pralatrexate

In an early phase trial with pralatrexate, a higher CR was observed in patients with PTCL compared with those of B-cell lymphoma at the cost of significant mucositis75. This toxicity was later found to be alleviated by the administration of vitamin B12 and folic acid.

In the PROPEL (Pralatrexate in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma) trial, a total of 111 patients with rrPTCL received pralatrexate at a dose of 30 mg/m2 for six out of seven weeks along with vitamin B12 and folic acid76. Among 109 evaluable patients, 12 CRs (11%) and 20 PRs (18%) were noted. The median duration of response and the median OS were 10.1 and 14.5 months, respectively. The most common grade 3–4 toxicities were thrombocytopenia (32%), mucositis (22%), neutropenia (22%), and anemia (18%), but pralatrexate was well tolerated, as the overall dose intensity was 80%. In the Japanese trial with the same dose and schedule, nine (45%) out of 20 evaluable patients achieved an objective response, and grade 3–4 thrombocytopenia occurred in 40% of cases77.

Based on the synergism pralatrexate has shown in preclinical analyses78,79, several combinations with it have been evaluated. In a phase II trial, a front-line combination of cyclophosphamide, etoposide, vincristine, and prednisone (CEOP) alternating with pralatrexate was evaluated in 33 patients with untreated PTCL80. Seventeen CRs (52%) and six PRs (18%) were achieved, and 15 patients received ASCT. The two-year PFS and OS rates were 39% and 60%, respectively, similar to outcomes with CHOP. Grade 3–4 anemia (27%), febrile neutropenia (18%), mucositis (18%), and thrombocytopenia (12%) occurred. In a phase I trial, pralatrexate followed by gemcitabine was administered in 34 patients with relapsed or refractory lymphoproliferative malignancies, among whom 11 patients with PTCL were included81. Of the 33 patients who were evaluable for response, seven (21%) showed a partial response, and two of the seven had T-cell lymphoma. In another case series, five elderly patients with rrPTCL received weekly administration of pralatrexate (15 mg/m2) and bortezomib (1.3 mg/m2) for three out of four weeks until progression82. One patient achieved CR after four cycles, which lasted over 12 months.

Several pralatrexate-based combinations, including CHOP (NCT02594267), pembrolizumab plus decitabine (NCT03240211), romidepsin (NCT01947140), and durvalumab (NCT03161223), are under evaluation.

Histone deacetylase inhibitors

Histone deacetylase (HDAC) inhibitors demonstrate anti-tumor efficacy by upregulating the expression of genes for cell cycle regulators, cell type-specific differentiation, and pro-apoptotic proteins83,84. Various classes of HDACs with clinical significance are expressed in patients with PTCL85,86. Two agents have been approved by the US Food and Drug Administration for treatment of PTCL: romidepsin (2011) and belinostat (2014).

Romidepsin

Romidepsin is a cyclic tetrapeptide-derived class-I selective HDAC inhibitor. After favorable outcomes were observed in an early phase trial87, a phase II trial was carried out in 47 patients with rrPTCL88. Romidepsin was administered in three out of four weeks with a starting dose of 14 mg/m2, which could be escalated up to 17.5 mg/m2 in the absence of toxicity. Among 45 evaluable patients, eight (18%) experienced CR and nine (20%) experienced PR. Thrombocytopenia was observed in 47% of patients; of note, Epstein-Barr virus (EBV)-associated lymphoproliferative disorder emerged in two patients. In the pivotal phase II trial89, a total of 131 patients with rrPTCL received romidepsin at a dose of 14 mg/m2 for three out of four weeks. Among 130 evaluable patients, 19 (15%) experienced CR and 14 (10%) experienced PR. Rapid responses were observed, and median time to response was 1.8 months and median time to CR was 3.7 months. In the 19 patients who achieved CR, the median PFS was 18 months. Grade 3–4 thrombocytopenia and neutropenia occurred in 23% and 18% of cases, respectively. The updated efficacy data demonstrated that, of the 19 patients who achieved CR, 10 had long-term (at least 12 months) responses90. In the phase II part of the Japanese trial, 40 patients with rrPTCL received 14 mg/m2 of romidepsin91. The CR rate was 25% (10/40), and the PR rate was 18% (7/40). Treatment-related adverse events led to discontinuation of romidepsin in 26% of patients.

Interestingly, an in vivo and in vitro study has suggested a role for romidepsin in the treatment of EBV-associated cancer, where it can induce the EBV lytic cycle92. In a Korean pilot study, however, three out of five patients with NK/T-cell lymphoma experienced EBV reactivation after romidepsin treatment93. This finding is consistent with the findings from the aforementioned two cases of EBV-associated lymphoproliferative disorder88. Thus, EBV-reactivation should be taken into account when using romidepsin to treat EBV-associated lymphoma.

Several romidepsin-based regimens are being evaluated. In the front-line setting, romidepsin plus CHOP was administered in 37 patients with PTCL65. Although hematologic toxicities precluded the completion of the planned treatment in 18% of patients, the CR rate was 51%, the PR rate was 17%, and the OS rate at 30 months was 70.7%. Prospective trials with romidepsin plus CHOP (NCT01796002) or CHOEP-21 (NCT02223208) are ongoing.

In the salvage setting, romidepsin at 12 mg/m2 (days 1, 8, and 15) with gemcitabine at 800 mg/m2 (days 1 and 15) up to six cycles, followed by romidepsin maintenance (at 14 mg/m2), was given to 20 patients with rrPTCL94. The clinical outcomes of the combination were a little better than those with monotherapy; the CR rate and the ORR were 15% and 30%, respectively. Another phase I study of romidepsin, gemcitabine, dexamethasone, and cisplatin was carried out by a Canadian group95, and of the 10 patients with PTCL, five responded. In addition, when romidepsin was added to ICE96, the CR rate was 64% (9/14) and the ORR was 78% (11/14). However, grade 3–4 thrombocytopenia and neutropenia occurred in 95% and 84% of the cycles, respectively.

Belinostat

Belinostat is a hydroxamic acid-derived, pan-HDAC inhibitor that demonstrates high affinity for the class I and II HDACs. In an early phase II trial, 24 patients with rrPTCL received belinostat, the ORR was 25% (6/24), and two patients experienced CR97. In the phase II BELIEF (A Multicenter, Open Label Trial of Belinostat in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma) trial, 129 patients with rrPTCL were enrolled to receive belinostat at 1,000 mg/m2 for five days every three weeks98. Among 120 evaluable patients, 13 achieved CR (11%) and 18 achieved PR (15%), and the ORR was 26%. In patients with CR, the median DoR exceeded 29 months. A subtype analysis revealed that, among 22 patients with AITL, the ORR was 45% (four CRs and six PRs)99. Most adverse events—nausea (42%), fatigue (37%), and pyrexia (35%)—were non-hematologic. Only 7% and 10% of patients experienced grade 3–4 thrombocytopenia and anemia, respectively.

These favorable hematologic toxicities provided momentum for initiating the next combination trial. In a phase I trial, belinostat at a dose of 1,000 mg/m2 for five days every three weeks was combined with CHOP for six cycles in 23 patients with untreated PTCL100. The combination was well tolerated; 18 patients (78%) completed six cycles. Among 21 evaluable patients, the ORR was 86% (n = 18), and most patients comprising the ORR were CR (n = 14, 67%).

Chidamide

Chidamide is an orally administered benzamide class of HDAC that demonstrates selective inhibition of HDAC1, 2, 3, and 10101. In a phase II trial, 83 patients with rrPTCL took 30 mg of chidamide twice weekly102. Among 79 evaluable patients, 11 CRs (14%) and 12 PRs (15%) were noted, and the median time to response was 1.4 months and the median DoR was 9.9 months. Grade 3–4 thrombocytopenia occurred in 22% of patients, and neutropenia occurred in 11% of patients. On the basis of these results, the Chinese Food and Drug Administration approved the use of chidamide to treat rrPTCL in 2014. Subsequently, large-scale real-world data were recently released103. Chidamide monotherapy resulted in an ORR of 39% (100/256) and a CR rate of 9% (27/256). Chidamide-based combination therapies demonstrated the highest ORR (51%, 65/127) and CR rate (12%, 15/127). In the monotherapy group, grade 3–4 thrombocytopenia occurred in 10.2% of cases and neutropenia occurred in 6.2% of cases. The real-world data demonstrated clinical outcomes similar to those of the phase II trial. Several trials with chidamide-based combinations (NCT02809573, NCT02987244, NCT02856997, and NCT03023358) are ongoing.

Other histone deacetylase inhibitors

Vorinostat is an orally administered benzamide HDAC inhibitor of class I–II. In a front-line setting, a combination of vorinostat plus CHOP demonstrated 79% and 81% of two-year PFS and OS rate, respectively104. In a relapsed or refractory setting, a combination of vorinostat, lenalidomide, and dexamethasone (40 mg once daily) was explored105, but the outcomes were not remarkable.

Panobinostat is an orally administered pan-HDAC inhibitor. In a phase II study106, 25 patients with rrPTCL or ENKTL received panobinostat at a dose of 20 mg three times a week and bortezomib at a dose of 1.3 mg/m2. The ORR was 43% (10/23), and the CR rate was 22% (5/23). Common treatment-related grade 3–4 toxicities were thrombocytopenia (68%), neutropenia (36%), and diarrhea (28%).

Immunomodulatory drugs

Lenalidomide shows anti-lymphoma efficacy through immune modulation of the microenvironment and anti-proliferative and anti-angiogenic mechanisms107. Two trials have investigated single-agent lenalidomide for 21 out of 28 days in patients with rrPTCL108,109. The CR rate ranged from 8% to 30%, and the ORR ranged from 22% to 30%. A substantial portion of patients (26–35%) experienced toxicities and this led to treatment discontinuation. Outcomes in patients with AITL, compared with other subtypes, were unique108 and this suggests a role for the microenvironment in this subtype. In a phase I/II trial, a combination of romidepsine, lenalidomide, and carfilzomib was tried in patients with rrPTCL110. In 16 evaluable patients, the CR rate was 31% (5/16) and the PR rate was 19% (3/16). Again, four out of five patients with AITL attained CR. A phase II study for untreated PTCL patients using lenalidomide plus romidepsin (NCT02232516) is ongoing.

Thalidomide, a prototype drug of this class, was evaluated for combination treatment. A combination of gemcitabine, cisplatin, prednisone, and thalidomide (GDPT) was compared with CHOP for patients with newly diagnosed PTCL111. In total, 103 patients were randomly allocated into two groups; 52 received GDPT and 51 received CHOP. The PFS, the primary end-point of the study, was significantly better in the GDPT arm; the two-year PFS rates were 57% versus 35% (P <0.05). Other outcomes, including the ORR (67% versus 49%, P = 0.046) and the two-year OS (71% versus 50%, P <0.05), were also favorable for the GDPT arm. Grade 3–4 myelosuppression occurred in 44% versus 41% of patients.

Proteasome inhibitors

In a phase II trial, the single-agent bortezomib induced an ORR of 67% in 15 patients with rrCTCL112. Because a chemosensitization effect was expected113, the efficacy of bortezomib was explored in combination with CHOP in patients with newly diagnosed PTCL/ENKTL/CTCL114. Of the 65 patients, 30 achieved CR (65%) and five other patients achieved PR. The ORR was 76% (35/46). When only three major subtypes of PTCLs (PTCL-NOS, AITL, and ALCL) were analyzed, the CR rate was 73% and the ORR was 87%. However, owing to frequent relapse after remission, the three-year OS and PFS rates were 47% and 35%, respectively. In another trial by the French group, the combination of bortezomib plus intensified CHOP-like regimen (ACVBP) was studied in 57 patients with newly diagnosed PTCL115. The outcomes did not appear to be higher than chemotherapy alone, as the CR rate was 45%.

A newer, irreversible proteasome inhibitor (carfilzomib) is currently under investigation in patients with PTCL (NCT01336920 and NCT03141203). Ixazomib, an oral proteasome inhibitor, is being assessed in a phase 2 study (NCT02158975).

Inhibitors of PI3K/mTOR pathways

PI3Ks transduce signals from various growth factors and cytokines into intracellular molecules by generating phospholipids, which then activate downstream effectors such as AKT or mTOR116.

Duvelisib, a dual inhibitor of PI3Kγ and δ, was studied in a phase 1 trial in patients with hematologic malignancies117. Among 15 evaluable patients with rrPTCL, the ORR was 47% (7/15, two CRs and five PRs) and the median OS was 36.4 weeks. A study of duvelisib with either romidepsin or bortezomib in T-cell lymphoma is under way (NCT02783625). Another PI3K δ/γ inhibitor, RP6530, was investigated in patients with relapsed or refractory T-cell lymphoma118. Among 14 evaluable patients, one CR (7%) and four PRs (29%) were noted. Copanlisib, a pan-class I inhibitor, was administered at a dose of 0.8 mg/kg on days 1, 8, and 15 of a 28-day cycle in a phase II study in which 17 patients with PTCL were included, and the ORR was 21.4%119. A phase I/II study for combination of copanlisib plus gemcitabine in rrPTCL is ready to begin (NCT03052933).

Given that a substantial portion of patients with PTCL show phospho-AKT overexpression, which confers a poor prognosis120, AKT can be a reasonable target. In a phase II trial with MK2206, however, a frustrating result was observed; none of the three patients with PTCL responded121.

Activation of mTOR induces cell growth and survival in cancer, and especially in lymphoma, Myc activity is known to depend on the mTOR pathway122. In a phase II study of 30 patients with untreated PTCL who received everolimus plus CHOP123, CR was observed in 17 (57%) and PR was observed in 10 (33%). Despite these favorable tumor responses, frequent relapses were noted as the two-year PFS rate was 33%. Single-agent everolimus in 16 patients with relapsed or refractory T-cell lymphoma demonstrated an ORR of 44% and a median DoR of 8.5 months124.

Alternative agents

Bendamustine

Bendamustine, which contains the structures of both alkylating agents and purine analogs, is one of the standard agents in indolent B-cell lymphoma. In the phase II BENTLY (Bendamustine in Patients With Refractory or Relapsed T-cell Lymphoma) trial, 60 patients with refractory or relapsed T-cell lymphoma received bendamustine at a dose of 120 mg/m2 for two consecutive days every three weeks for up to six cycles125. With the majority of patients having AITL and PTCL-NOS (91%), the ORR was 50% and the median DoR was 3.5 months. Major grade 3–4 toxicities were neutropenia (30%), thrombocytopenia (24%), and infection (20%). In the phase II BENCART (Bendamustine, Carboplatin and Dexamethasone for Refractory or Relapsed Peripheral T-Cell Lymphoma) trial, 30 patients with rrPTCL received a combination of bendamustine, carboplatin, and dexamethasone to proceed to ASCT126. Among 28 evaluable patients, eight CRs (30%) and seven PRs (25%) were observed. The median PFS was 4.8 months.

Aurora-A kinase inhibitors

Aurora-A is a mitotic kinase overexpressed in several subtypes of PTCL127. Alisertib, a small-molecule inhibitor of aurora-A kinase, has demonstrated favorable anti-tumor efficacy against rrPTCL in two phase II trials128,129. Given the promising results, a phase III LUMIERE (Alisertib or Investigator's Choice in Patients With Relapsed/Refractory Peripheral T-Cell Lymphoma) trial was performed in patients with rrPTCL to compare the efficacy of alisertib versus the investigator’s choice, including pralatrexate, romidepsin, or gemcitabine130. With a planned accrual of 271 patients, interim analyses were carried out after 238 patients were recruited. ORRs, the primary end-points of the study, were 33% for alisertib and 43% for the investigator’s choice130. In addition, no benefit was observed across the safety profiles. With these results, the trial was prematurely terminated.

Tipifarnib

Tipifarnib is an orally administered nonpeptidomimetic farnesyl transferase inhibitor. In a phase II trial, 93 patients, including 16 patients with T-cell lymphoma, received tipifarnib 300 mg twice daily for three out of four weeks131. A higher response rate was observed in the T-cell/Hodgkin’s lymphoma cohort (31%) compared with the aggressive (17%) or indolent (7%) B-cell lymphoma cohorts. Among eight patients with PTCL-NOS, three achieved CR and one achieved PR. Based on these promising results, a phase II trial was carried out solely on patients with rrPTCL, and the preliminary results were recently reported132. A total of 18 patients received tipifarnib at a dose of 600 mg twice daily on days 1–7 and 15–21 in 28-day cycles, which demonstrated three PRs (17%) at the cost of grade 3–4 neutropenia (83%) and thrombocytopenia (61%).

CPI-613

CPI-613 is a novel lipoate derivative that inhibits mitochondrial metabolism in cancer cells133. In a phase I trial in patients with hematologic malignancies, the maximum tolerated dose was determined to be 2,940 mg/m2, a major toxicity was renal failure134. In another phase I trial in patients with relapsed or refractory T-cell lymphoma, bendamustine plus CPI-613 was administered135. Out of five evaluable patients, three CRs and one PR were observed.

Conclusions

Despite recent progress, there are hurdles to overcome in managing patients with PTCL, such as the poorly understood role of certain molecular features. Given the insufficient clinical outcomes out of the current standard of care, there are still unmet needs for the novel therapy.

Owing to the introduction of novel therapeutic agents however, recent outcomes are worthy of attention. Tailored clinical approaches regarding what drugs to initiate, when to consolidate patients, and how to best salvage patients require further investigation, including prospective trials.

Competing interests

No competing interests were disclosed.

Grant information

The author(s) declared that no grants were involved in supporting this work.

F1000 recommended

References

  • 1.  Swerdlow SH, Campo E, Pileri SA, et al.: The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016; 127(20): 2375–2390. PubMed Abstract | Publisher Full Text | Free Full Text
  • 2.  A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood. 1997; 89(11): 3909–18. PubMed Abstract
  • 3.  Coiffier B, Brousse N, Peuchmaur M, et al.: Peripheral T-cell lymphomas have a worse prognosis than B-cell lymphomas: a prospective study of 361 immunophenotyped patients treated with the LNH-84 regimen. The GELA (Groupe d'Etude des Lymphomes Agressives). Ann Oncol. 1990; 1(1): 45–50. PubMed Abstract
  • 4.  Attygalle A, Al-Jehani R, Diss TC, et al.: Neoplastic T cells in angioimmunoblastic T-cell lymphoma express CD10. Blood. 2002; 99(2): 627–33. PubMed Abstract | Publisher Full Text
  • 5.  de Leval L, Rickman DS, Thielen C, et al.: The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells. Blood. 2007; 109(11): 4952–63. PubMed Abstract | Publisher Full Text
  • 6.  Marafioti T, Paterson JC, Ballabio E, et al.: The inducible T-cell co-stimulator molecule is expressed on subsets of T cells and is a new marker of lymphomas of T follicular helper cell-derivation. Haematologica. 2010; 95(3): 432–9. PubMed Abstract | Publisher Full Text | Free Full Text
  • 7.  Lemonnier F, Couronné L, Parrens M, et al.: Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters. Blood. 2012; 120(7): 1466–9. PubMed Abstract | Publisher Full Text
  • 8.  Yoo HY, Sung MK, Lee SH, et al.: A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma. Nat Genet. 2014; 46(4): 371–5. PubMed Abstract | Publisher Full Text | F1000 Recommendation
  • 9.  Palomero T, Couronné L, Khiabanian H, et al.: Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat Genet. 2014; 46(2): 166–70. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
  • 10.  Sakata-Yanagimoto M, Enami T, Yoshida K, et al.: Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat Genet. 2014; 46(2): 171–5. PubMed Abstract | Publisher Full Text | F1000 Recommendation
  • 11.  Cairns RA, Iqbal J, Lemonnier F, et al.: IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma. Blood. 2012; 119(8): 1901–3. PubMed Abstract | Publisher Full Text | Free Full Text
  • 12.  Iqbal J, Wright G, Wang C, et al.: Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma. Blood. 2014; 123(19): 2915–23. PubMed Abstract | Publisher Full Text | Free Full Text
  • 13.  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(12): 5496–504. PubMed Abstract | Publisher Full Text
  • 14.  Parrilla Castellar ER, Jaffe ES, Said JW, et al.: ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes. Blood. 2014; 124(9): 1473–80. PubMed Abstract | Publisher Full Text | Free Full Text
  • 15.  Keech JA Jr, Creech BJ: Anaplastic T-cell lymphoma in proximity to a saline-filled breast implant. Plast Reconstr Surg. 1997; 100(2): 554–5. PubMed Abstract
  • 16.  Miranda RN, Aladily TN, Prince HM, et al.: Breast implant-associated anaplastic large-cell lymphoma: long-term follow-up of 60 patients. J Clin Oncol. 2014; 32(2): 114–20. PubMed Abstract | Publisher Full Text | Free Full Text
  • 17.  Laurent C, Delas A, Gaulard P, et al.: Breast implant-associated anaplastic large cell lymphoma: two distinct clinicopathological variants with different outcomes. Ann Oncol. 2016; 27(2): 306–14. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
  • 18.  Tan SY, Ooi AS, Ang MK, et al.: Nuclear expression of MATK is a novel marker of type II enteropathy-associated T-cell lymphoma. Leukemia. 2011; 25(3): 555–7. PubMed Abstract | Publisher Full Text
  • 19.  Tan SY, Chuang SS, Tang T, et al.: Type II EATL (epitheliotropic intestinal T-cell lymphoma): a neoplasm of intra-epithelial T-cells with predominant CD8αα phenotype. Leukemia. 2013; 27(8): 1688–96. PubMed Abstract | Publisher Full Text
  • 20.  Roberti A, Dobay MP, Bisig B, et al.: Type II enteropathy-associated T-cell lymphoma features a unique genomic profile with highly recurrent SETD2 alterations. Nat Commun. 2016; 7: 12602. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
  • 21.  Perry AM, Warnke RA, Hu Q, et al.: Indolent T-cell lymphoproliferative disease of the gastrointestinal tract. Blood. 2013; 122(22): 3599–606. PubMed Abstract | Publisher Full Text | Free Full Text
  • 22.  Margolskee E, Jobanputra V, Lewis SK, et al.: Indolent small intestinal CD4+ T-cell lymphoma is a distinct entity with unique biologic and clinical features. PLoS One. 2013; 8(7): e68343. PubMed Abstract | Publisher Full Text | Free Full Text
  • 23.  Horwitz SM, Zelenetz AD, Gordon LI, et al.: NCCN Guidelines Insights: Non-Hodgkin's Lymphomas, Version 3.2016. J Natl Compr Canc Netw. 2016; 14(9): 1067–79. PubMed Abstract | Publisher Full Text | F1000 Recommendation
  • 24.  d'Amore F, Gaulard P, Trümper L, et al.: Peripheral T-cell lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015; 26 Suppl 5: v108–15. PubMed Abstract | Publisher Full Text
  • 25.  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(10): 1467–75. PubMed Abstract | Publisher Full Text
  • 26.  Vose J, Armitage J, Weisenburger D, et al.: International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008; 26(25): 4124–30. PubMed Abstract | Publisher Full Text | F1000 Recommendation
  • 27.  Abouyabis AN, Shenoy PJ, Sinha R, et al.: A Systematic Review and Meta-Analysis of Front-line Anthracycline-Based Chemotherapy Regimens for Peripheral T-Cell Lymphoma. ISRN Hematol. 2011; 2011: 623924. PubMed Abstract | Publisher Full Text | Free Full Text
  • 28.  Escalón MP, Liu NS, Yang Y, et al.: Prognostic factors and treatment of patients with T-cell non-Hodgkin lymphoma: the M. D. Anderson Cancer Center experience. Cancer. 2005; 103(10): 2091–8. PubMed Abstract | Publisher Full Text
  • 29.  Peng YL, Huang HQ, Lin XB, et al.: [Clinical outcomes of patients with peripheral T-cell lymphoma (PTCL) treated by EPOCH regimen]. Ai Zheng. 2004; 23(8): 943–6. PubMed Abstract
  • 30.  Simon A, Peoch M, Casassus P, et al.: Upfront VIP-reinforced-ABVD (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 Haematol. 2010; 151(2): 159–66. PubMed Abstract | Publisher Full Text
  • 31.  Tilly H, Lepage E, Coiffier B, et al.: Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. Blood. 2003; 102(13): 4284–9. PubMed Abstract | Publisher Full Text
  • 32.  Niitsu N, Hayama M, Yoshino T, et al.: Multicentre phase II study of the CyclOBEAP regimen for patients with peripheral T-cell lymphoma with analysis of biomarkers. Br J Haematol. 2011; 153(5): 582–8. PubMed Abstract | Publisher Full Text
  • 33.  Pfreundschuh M, Trümper L, Kloess M, et al.: Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL. Blood. 2004; 104(3): 626–33. PubMed Abstract | Publisher Full Text
  • 34.  Pfreundschuh M, Trümper L, Kloess M, et al.: Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood. 2004; 104(3): 634–41. PubMed Abstract | Publisher Full Text
  • 35.  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(2): 371–9. PubMed Abstract | Publisher Full Text | Free Full Text
  • 36.  Kim JG, Sohn SK, Chae YS, et al.: CHOP plus etoposide and gemcitabine (CHOP-EG) as front-line chemotherapy for patients with peripheral T cell lymphomas. Cancer Chemother Pharmacol. 2006; 58(1): 35–9. PubMed Abstract | Publisher Full Text
  • 37.  Gleeson M, Peckitt C, To YM, et al.: CHOP VERSUS GEM-P IN THE FIRST-LINE TREATMENT OF T-CELL LYMPHOMA (PTCL): INITIAL RESULTS OF THE UK NRCI PHASE II RANDOMISED CHEMO-T TRIAL. Hematol Oncol. 2017; 35: 75–6. Publisher Full Text
  • 38.  Reimer P, Rüdiger 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(1): 106–13. PubMed Abstract | Publisher Full Text
  • 39.  d'Amore F, Relander T, Lauritzsen GF, et al.: Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01. J Clin Oncol. 2012; 30(25): 3093–9. PubMed Abstract | Publisher Full Text | F1000 Recommendation
  • 40.  d'Amore F, Relander T, Lauritzsen G, et al.: TEN YEARS MEDIAN FOLLOW-UP OF THE NORDIC NLG-T-01 TRIAL ON CHOEP AND UPFRONT AUTOLOGOUS TRANSPLANTATION IN PERIPHERAL T-CELL LYMPHOMAS. Hematol Oncol. 2015; 33: 139–140, [Internet]. Reference Source
  • 41.  Norbert Schmitz MN, Altmann B, Ziepert M, et al.: Allogeneic or autologous transplantation as first-line therapy for younger patients with peripheral T-cell lymphoma: Results of the interim analysis of the AATT trial. ASCO annual meeting. J Clin Oncol. 2015; 33(15_suppl): 8507–8507. Reference Source
  • 42.  Beitinjaneh A, Saliba RM, Medeiros LJ, et al.: Comparison of survival in patients with T cell lymphoma after autologous and allogeneic stem cell transplantation as a frontline strategy or in relapsed disease. Biol Blood Marrow Transplant. 2015; 21(5): 855–9. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
  • 43.  Mak V, Hamm J, Chhanabhai M, et al.: Survival of patients with peripheral T-cell lymphoma after first relapse or progression: spectrum of disease and rare long-term survivors. J Clin Oncol. 2013; 31(16): 1970–6. PubMed Abstract | Publisher Full Text | F1000 Recommendation
  • 44.  Enblad G, Hagberg H, Erlanson M, et al.: A pilot study of alemtuzumab (anti-CD52 monoclonal antibody) therapy for patients with relapsed or chemotherapy-refractory peripheral T-cell lymphomas. Blood. 2004; 103(8): 2920–4. PubMed Abstract | Publisher Full Text
  • 45.  Kim SJ, Kim K, Kim BS, et al.: Alemtuzumab and DHAP (A-DHAP) is effective for relapsed peripheral T-cell lymphoma, unspecified: interim results of a phase II prospective study. Ann Oncol. 2009; 20(2): 390–2. PubMed Abstract | Publisher Full Text
  • 46.  Weidmann E, Hess G, Chow KU, et al.: A phase II study of alemtuzumab, fludarabine, cyclophosphamide, and doxorubicin (Campath-FCD) in peripheral T-cell lymphomas. Leuk Lymphoma. 2010; 51(3): 447–55. PubMed Abstract | Publisher Full Text
  • 47.  Ravandi F, Aribi A, O'Brien S, et al.: Phase II study of alemtuzumab in combination with pentostatin in patients with T-cell neoplasms. J Clin Oncol. 2009; 27(32): 5425–30. PubMed Abstract | Publisher Full Text | Free Full Text
  • 48.  Kim JG, Sohn SK, Chae YS, et al.: Alemtuzumab plus CHOP as front-line chemotherapy for patients with peripheral T-cell lymphomas: a phase II study. Cancer Chemother Pharmacol. 2007; 60(1): 129–34. PubMed Abstract | Publisher Full Text
  • 49.  Kluin-Nelemans HC, van Marwijk Kooy M, Lugtenburg PJ, et al.: Intensified alemtuzumab-CHOP therapy for peripheral T-cell lymphoma. Ann Oncol. 2011; 22(7): 1595–600. PubMed Abstract | Publisher Full Text
  • 50.  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(7): 2316–23. PubMed Abstract | Publisher Full Text
  • 51.  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(11): 1521–8. PubMed Abstract | Publisher Full Text | Free Full Text
  • 52.  Pro B, Advani R, Brice P, et al.: Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012; 30(18): 2190–6. PubMed Abstract | Publisher Full Text
  • 53.  Pro B, Advani R, Brice P, et al.: Four-Year Survival Data from an Ongoing Pivotal Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma. American Society of Hematology 56th Annual Meeting (2014), Blood. 2014; 124(21): 3095. Reference Source
  • 54.  Pro B, Advani RH, Brice P, et al.: Five-Year Survival Data from a Pivotal Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma. American Society of Hematology 58th Annual Meeting (2016), Blood. 2016; 128(22): 4144. Reference Source
  • 55.  Weisenburger DD, Savage KJ, Harris NL, et al.: Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project. Blood. 2011; 117(12): 3402–8. PubMed Abstract | Publisher Full Text
  • 56.  Murray A, Cuevas EC, Jones DB, et al.: Study of the immunohistochemistry and T cell clonality of enteropathy-associated T cell lymphoma. Am J Pathol. 1995; 146(2): 509–19. PubMed Abstract | Free Full Text
  • 57.  Schwartz EJ, Molina-Kirsch H, Zhao S, et al.: Immunohistochemical characterization of nasal-type extranodal NK/T-cell lymphoma using a tissue microarray: an analysis of 84 cases. Am J Clin Pathol. 2008; 130(3): 343–51. PubMed Abstract | Publisher Full Text
  • 58.  Horwitz SM, Advani RH, Bartlett NL, et al.: Objective responses in relapsed T-cell lymphomas with single-agent brentuximab vedotin. Blood. 2014; 123(20): 3095–100. PubMed Abstract | Publisher Full Text | Free Full Text
  • 59.  Fanale MA, Horwitz SM, Forero-Torres A, et al.: Brentuximab vedotin in the front-line treatment of patients with CD30+ peripheral T-cell lymphomas: results of a phase I study. J Clin Oncol. 2014; 32(28): 3137–43. PubMed Abstract | Publisher Full Text | Free Full Text
  • 60.  Fanale MA, Horwitz SM, Forero-Torres A, et al.: Four-Year Survival and Durability Results of Brentuximab Vedotin in Combination with CHP in the Frontline Treatment of Patients with CD30-Expressing Peripheral T-Cell Lymphomas. American Society of Hematology 58th Annual Meeting (2016), Blood. 2016; 128(22): 2993. Reference Source
  • 61.  Ishida T, Utsunomiya A, Iida S, et al.: Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: its close association with skin involvement and unfavorable outcome. Clin Cancer Res. 2003; 9(10 Pt 1): 3625–34. PubMed Abstract
  • 62.  Ishida T, Inagaki H, Utsunomiya A, et al.: CXC chemokine receptor 3 and CC chemokine receptor 4 expression in T-cell and NK-cell lymphomas with special reference to clinicopathological significance for peripheral T-cell lymphoma, unspecified. Clin Cancer Res. 2004; 10(16): 5494–500. PubMed Abstract | Publisher Full Text
  • 63.  Jones D, O'Hara C, Kraus MD, et al.: Expression pattern of T-cell-associated chemokine receptors and their chemokines correlates with specific subtypes of T-cell non-Hodgkin lymphoma. Blood. 2000; 96(2): 685–90. PubMed Abstract
  • 64.  Ogura M, Ishida T, Hatake K, et al.: Multicenter phase II study of mogamulizumab (KW-0761), a defucosylated anti-cc chemokine receptor 4 antibody, in patients with relapsed peripheral T-cell lymphoma and cutaneous T-cell lymphoma. J Clin Oncol. 2014; 32(11): 1157–63. PubMed Abstract | Publisher Full Text
  • 65.  Dupuis J, Morschhauser F, Ghesquières H, et al.: Combination of romidepsin with cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated patients with peripheral T-cell lymphoma: a non-randomised, phase 1b/2 study. Lancet Haematol. 2015; 2(4): e160–5. PubMed Abstract | Publisher Full Text | F1000 Recommendation
  • 66.  Yamamoto R, Nishikori M, Kitawaki T, et al.: PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. Blood. 2008; 111(6): 3220–4. PubMed Abstract | Publisher Full Text
  • 67.  Mittal S, Marshall NA, Duncan L, et al.: Local and systemic induction of CD4+CD25+ regulatory T-cell population by non-Hodgkin lymphoma. Blood. 2008; 111(11): 5359–70. PubMed Abstract | Publisher Full Text
  • 68.  Dorfman DM, Brown JA, Shahsafaei A, et al.: Programmed death-1 (PD-1) is a marker of germinal center-associated T cells and angioimmunoblastic T-cell lymphoma. Am J Surg Pathol. 2006; 30(7): 802–10. PubMed Abstract | Publisher Full Text | Free Full Text
  • 69.  Chen BJ, Chapuy B, Ouyang J, et al.: PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res. 2013; 19(13): 3462–73. PubMed Abstract | Publisher Full Text | Free Full Text
  • 70.  Lesokhin AM, Ansell SM, Armand P, et al.: Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study. J Clin Oncol. 2016; 34(23): 2698–704. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
  • 71.  Chan TS, Khong PL, Kwong YL: Pembrolizumab for relapsed anaplastic large cell lymphoma after allogeneic haematopoietic stem cell transplantation: efficacy and safety. Ann Hematol. 2016; 95(11): 1913–5. PubMed Abstract | Publisher Full Text
  • 72.  Kwong YL, Chan TSY, Tan D, et al.: PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase. Blood. 2017; 129(17): 2437–42. PubMed Abstract | Publisher Full Text
  • 73.  Ansell S, Gutierrez ME, Shipp MA, et al.: A Phase 1 Study of Nivolumab in Combination with Ipilimumab for Relapsed or Refractory Hematologic Malignancies (CheckMate 039). 58th Annual Meeting of American Society of Hematology, 2016. Reference Source
  • 74.  Marchi E, Mangone M, Zullo K, et al.: Pralatrexate pharmacology and clinical development. Clin Cancer Res. 2013; 19(24): 6657–61. PubMed Abstract | Publisher Full Text
  • 75.  O'Connor OA, Horwitz S, Hamlin P, et al.: Phase II-I-II study of two different doses and schedules of pralatrexate, a high-affinity substrate for the reduced folate carrier, in patients with relapsed or refractory lymphoma reveals marked activity in T-cell malignancies. J Clin Oncol. 2009; 27(26): 4357–64. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
  • 76.  O'Connor OA, Pro B, Pinter-Brown L, et al.: Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol. 2011; 29(9): 1182–9. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
  • 77.  Maruyama D, Nagai H, Maeda Y, et al.: Phase I/II study of pralatrexate in Japanese patients with relapsed or refractory peripheral T-cell lymphoma. Cancer Sci. 2017; 108(10): 2061–8. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
  • 78.  Toner LE, Vrhovac R, Smith EA, et al.: The schedule-dependent effects of the novel antifolate pralatrexate and gemcitabine are superior to methotrexate and cytarabine in models of human non-Hodgkin's lymphoma. Clin Cancer Res. 2006; 12(3 Pt 1): 924–32. PubMed Abstract | Publisher Full Text
  • 79.  Marchi E, Paoluzzi L, Scotto L, et al.: Pralatrexate is synergistic with the proteasome inhibitor bortezomib in in vitro and in vivo models of T-cell lymphoid malignancies. Clin Cancer Res. 2010; 16(14): 3648–58. PubMed Abstract | Publisher Full Text
  • 80.  Advani RH, Ansell SM, Lechowicz MJ, et al.: A phase II study of cyclophosphamide, etoposide, vincristine and prednisone (CEOP) Alternating with Pralatrexate (P) as front line therapy for patients with peripheral T-cell lymphoma (PTCL): final results from the T- cell consortium trial. Br J Haematol. 2016; 172(4): 535–44. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
  • 81.  Horwitz SM, Vose JM, Advani R, et al.: Pralatrexate and Gemcitabine in Patients with Relapsed or Refractory Lymphoproliferative Malignancies: Phase 1 Results. (#1674). Annual Meeting of American Society of Hematology. Blood. 2009; 114(22): 1674. Reference Source
  • 82.  Lee SS, Jung SH, Ahn JS, et al.: Pralatrexate in Combination with Bortezomib for Relapsed or Refractory Peripheral T Cell Lymphoma in 5 Elderly Patients. J Korean Med Sci. 2016; 31(7): 1160–3. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
  • 83.  Marks PA, Richon VM, Rifkind RA: Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J Natl Cancer Inst. 2000; 92(15): 1210–6. PubMed Abstract | Publisher Full Text
  • 84.  Bolden JE, Peart MJ, Johnstone RW: Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov. 2006; 5(9): 769–84. PubMed Abstract | Publisher Full Text
  • 85.  Marquard L, Poulsen CB, Gjerdrum LM, et al.: Histone deacetylase 1, 2, 6 and acetylated histone H4 in B- and T-cell lymphomas. Histopathology. 2009; 54(6): 688–98. PubMed Abstract | Publisher Full Text
  • 86.  Gloghini A, Buglio D, Khaskhely NM, et al.: Expression of histone deacetylases in lymphoma: implication for the development of selective inhibitors. Br J Haematol. 2009; 147(4): 515–25. PubMed Abstract | Publisher Full Text | Free Full Text
  • 87.  Piekarz RL, Robey R, Sandor V, et al.: Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: a case report. Blood. 2001; 98(9): 2865–8. PubMed Abstract | Publisher Full Text
  • 88.  Piekarz RL, Frye R, Prince HM, et al.: Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood. 2011; 117(22): 5827–34. PubMed Abstract | Publisher Full Text | Free Full Text
  • 89.  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(6): 631–6. PubMed Abstract | Publisher Full Text | F1000 Recommendation
  • 90.  Coiffier B, Pro B, Prince HM, et al.: Romidepsin for the treatment of relapsed/refractory peripheral T-cell lymphoma: pivotal study update demonstrates durable responses. J Hematol Oncol. 2014; 7: 11. PubMed Abstract | Publisher Full Text | Free Full Text
  • 91.  Maruyama D, Tobinai K, Ogura M, et al.: Romidepsin in Japanese patients with relapsed or refractory peripheral T-cell lymphoma: a phase I/II and pharmacokinetics study. Int J Hematol. 2017; 106(5): 655–65. PubMed Abstract | Publisher Full Text | F1000 Recommendation
  • 92.  Hui KF, Cheung AK, Choi CK, et al.: Inhibition of class I histone deacetylases by romidepsin potently induces Epstein-Barr virus lytic cycle and mediates enhanced cell death with ganciclovir. Int J Cancer. 2016; 138(1): 125–36. PubMed Abstract | Publisher Full Text | F1000 Recommendation
  • 93.  Kim SJ, Kim JH, Ki CS, et al.: Epstein-Barr virus reactivation in extranodal natural killer/T-cell lymphoma patients: a previously unrecognized serious adverse event in a pilot study with romidepsin. Ann Oncol. 2016; 27(3): 508–13. PubMed Abstract | Publisher Full Text
  • 94.  Pellegrini C, Dodero A, Chiappella A, et al.: A phase II study on the role of gemcitabine plus romidepsin (GEMRO regimen) in the treatment of relapsed/refractory peripheral T-cell lymphoma patients. J Hematol Oncol. 2016; 9: 38. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
  • 95.  Reiman T, Savage KJ, Crump M, et al.: A Phase I Study of Romidepsin, Gemcitabine, Dexamethasone and Cisplatin Combination Therapy in the Treatment of Peripheral T-Cell and Diffuse Large B-Cell Lymphoma: Canadian Cancer Trials Group Study LY. Annual Meeting of American Society of Hematology, Blood. 2016; 128(22): 4162. Reference Source
  • 96.  Chihara D, Oki Y, Westin JR, et al.: High Response Rate of Romidepsin in Combination with ICE (Ifosfamide, Carboplatin and Etoposide) in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma: Updates of Phase I Trial. Annual Meeting of American Society of Hematology. Blood. 2015; 126(23): 3987. Reference Source
  • 97.  Foss F, Advani R, Duvic M, et al.: A Phase II trial of Belinostat (PXD101) in patients with relapsed or refractory peripheral or cutaneous T-cell lymphoma. Br J Haematol. 2015; 168(6): 811–9. PubMed Abstract | Publisher Full Text | F1000 Recommendation
  • 98.  O'Connor OA, Horwitz S, Masszi T, et al.: Belinostat in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma: Results of the Pivotal Phase II BELIEF (CLN-19) Study. J Clin Oncol. 2015; 33(23): 2492–9. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
  • 99.  Horwitz S, OO C, Jurczak W, et al.: Belinostat in relapsed or refractory peripheral T-cell lymphoma (R/R PTCL) subtype angioimmunoblastic T-cell lymphoma (AITL): Results from the pivotal BELIEF trial. 12th International Conference on Malignant Lymphoma, 2013.
  • 100.  Johnston PB, Cashen AF, Nikolinakos PG, et al.: Safe and Effective Treatment of Patients with Peripheral T-Cell Lymphoma (PTCL) with the Novel HDAC Inhibitor, Belinostat, in Combination with CHOP: Results of the Bel-CHOP Phase 1 Trial. Annual Meeting of American Society of Hematology. Blood. 2015; 126(23): 253. Reference Source
  • 101.  Ning ZQ, Li ZB, Newman MJ, et al.: Chidamide (CS055/HBI-8000): a new histone deacetylase inhibitor of the benzamide class with antitumor activity and the ability to enhance immune cell-mediated tumor cell cytotoxicity. Cancer Chemother Pharmacol. 2012; 69(4): 901–9. PubMed Abstract | Publisher Full Text
  • 102.  Shi Y, Dong M, Hong X, et al.: Results from a multicenter, open-label, pivotal phase II study of chidamide in relapsed or refractory peripheral T-cell lymphoma. Ann Oncol. 2015; 26(8): 1766–71. PubMed Abstract | Publisher Full Text | F1000 Recommendation
  • 103.  Shi Y, Jia B, Xu W, et al.: Chidamide in relapsed or refractory peripheral T cell lymphoma: a multicenter real-world study in China. J Hematol Oncol. 2017; 10(1): 69. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
  • 104.  Oki Y, Younes A, Copeland A, et al.: Phase I study of vorinostat in combination with standard CHOP in patients with newly diagnosed peripheral T-cell lymphoma. Br J Haematol. 2013; 162(1): 138–41. PubMed Abstract | Publisher Full Text
  • 105.  Hopfinger G, Nösslinger T, Lang A, et al.: Lenalidomide in combination with vorinostat and dexamethasone for the treatment of relapsed/refractory peripheral T cell lymphoma (PTCL): report of a phase I/II trial. Ann Hematol. 2014; 93(3): 459–62. PubMed Abstract | Publisher Full Text
  • 106.  Goh YT, Hwang WY, Diong CP, et al.: A Phase 2 Study of Panobinostat (PAN) in Combination with Bortezomib (BTZ) in Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma (PTCL) or NK/T-Cell Lymphoma (NKL). Annual Meeting of American Society of Hematology, Blood. 2014; 124(21): 503. Reference Source
  • 107.  Kritharis A, Coyle M, Sharma J, et al.: Lenalidomide in non-Hodgkin lymphoma: biological perspectives and therapeutic opportunities. Blood. 2015; 125(16): 2471–6. PubMed Abstract | Publisher Full Text | Free Full Text
  • 108.  Morschhauser F, Fitoussi O, Haioun C, et al.: A phase 2, multicentre, single-arm, open-label study to evaluate the safety and efficacy of single-agent lenalidomide (Revlimid) in subjects with relapsed or refractory peripheral T-cell non-Hodgkin lymphoma: the EXPECT trial. Eur J Cancer. 2013; 49(13): 2869–76. PubMed Abstract | Publisher Full Text
  • 109.  Toumishey E, Prasad A, Dueck G, et al.: Final report of a phase 2 clinical trial of lenalidomide monotherapy for patients with T-cell lymphoma. Cancer. 2015; 121(5): 716–23. PubMed Abstract | Publisher Full Text | F1000 Recommendation
  • 110.  Mehta-Shah N, Moskowitz AJ, Lunning M, et al.: A Phase Ib/IIa Trial of the Combination of Romidepsin, Lenalidomide and Carfilzomib in Patients with Relapsed/Refractory Lymphoma Shows Complete Responses in Relapsed and Refractory T-Cell Lymphomas. Annual Meeting of American Society of Hematology, Blood. 2016; 128(22): 2991. Reference Source
  • 111.  Li L, Duan W, Zhang L, et al.: The efficacy and safety of gemcitabine, cisplatin, prednisone, thalidomide versus CHOP in patients with newly diagnosed peripheral T-cell lymphoma with analysis of biomarkers. Br J Haematol. 2017; 178(5): 772–80. PubMed Abstract | Publisher Full Text | F1000 Recommendation
  • 112.  Zinzani PL, Musuraca G, Tani M, et al.: Phase II trial of proteasome inhibitor bortezomib in patients with relapsed or refractory cutaneous T-cell lymphoma. J Clin Oncol. 2007; 25(27): 4293–7. PubMed Abstract | Publisher Full Text
  • 113.  Arlt A, Vorndamm J, Breitenbroich M, et al.: Inhibition of NF-kappaB sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin. Oncogene. 2001; 20(7): 859–68. PubMed Abstract | Publisher Full Text
  • 114.  Kim SJ, Yoon DH, Kang HJ, et al.: Bortezomib in combination with CHOP as first-line treatment for patients with stage III/IV peripheral T-cell lymphomas: a multicentre, single-arm, phase 2 trial. Eur J Cancer. 2012; 48(17): 3223–31. PubMed Abstract | Publisher Full Text
  • 115.  Delmer A, Fitoussi O, Gaulard P, et al.: A phase II study of bortezomib in combination with intensified CHOP-like regimen (ACVBP) in patients with previously untreated T-cell lymphoma: results of the GELA LNH05-1T trial. Annual Meeting of American Society of Clinical Oncology, J Clin Oncol. 2009; 27(15S): 8554. Reference Source
  • 116.  Liu P, Cheng H, Roberts TM, et al.: Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009; 8(8): 627–44. PubMed Abstract | Publisher Full Text | Free Full Text
  • 117.  Steven M, Horwitz PP, Flinn I, et al.: Duvelisib (IPI-145), a Phosphoinositide-3-Kinase-δ,γ Inhibitor, Shows Activity in Patients with Relapsed/Refractory T-Cell Lymphoma. Annual Meeting of American Society of Hematology. Blood. 2014; 124(21): 803. Reference Source
  • 118.  Oki Y, Zain J, Haverkos B, et al.: Dual Pi3k δ/γ Inhibitor Rp6530 In Patients With Relapsed/Refractory T-Cell Lymphoma: Dose Escalation Findings. Hematol Oncol. 2017; 35(Supplement S2): 412. Publisher Full Text
  • 119.  Dreyling M, Morschhauser F, Bouabdallah K, et al.: Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. Ann Oncol. 2017; 28(9): 2169–78. PubMed Abstract | Publisher Full Text | F1000 Recommendation
  • 120.  Hong JY, Hong ME, Choi MK, et al.: The clinical significance of activated p-AKT expression in peripheral T-cell lymphoma. Anticancer Res. 2015; 35(4): 2465–74. PubMed Abstract
  • 121.  Oki Y, Fanale M, Romaguera J, et al.: Phase II study of an AKT inhibitor MK2206 in patients with relapsed or refractory lymphoma. Br J Haematol. 2015; 171(4): 463–70. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
  • 122.  Pourdehnad M, Truitt ML, Siddiqi IN, et al.: Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers. Proc Natl Acad Sci U S A. 2013; 110(29): 11988–93. PubMed Abstract | Publisher Full Text | Free Full Text
  • 123.  Kim SJ, Shin DY, Kim JS, et al.: A phase II study of everolimus (RAD001), an mTOR inhibitor plus CHOP for newly diagnosed peripheral T-cell lymphomas. Ann Oncol. 2016; 27(4): 712–8. PubMed Abstract | Publisher Full Text
  • 124.  Witzig TE, Reeder C, Han JJ, et al.: The mTORC1 inhibitor everolimus has antitumor activity in vitro and produces tumor responses in patients with relapsed T-cell lymphoma. Blood. 2015; 126(3): 328–35. PubMed Abstract | Publisher Full Text | F1000 Recommendation
  • 125.  Damaj G, Gressin R, Bouabdallah K, et al.: Results from a prospective, open-label, phase II trial of bendamustine in refractory or relapsed T-cell lymphomas: the BENTLY trial. J Clin Oncol. 2013; 31(1): 104–10. PubMed Abstract | Publisher Full Text
  • 126.  Park B, Kim W, Suh C, et al.: A Phase II Trial Of Bendamustine, Carboplatin And Dexamethasone (BCD) For Refractory Or Relapsed Peripheral T-Cell Lymphoma (BENCART): A Consortium For Improving Survival Of Lymphoma (CISL) Trial. Hematol Oncol. 2017; 35(S2): 393–4. Publisher Full Text
  • 127.  Kanagal-Shamanna R, Lehman NL, O'Donnell JP, et al.: Differential expression of aurora-A kinase in T-cell lymphomas. Mod Pathol. 2013; 26(5): 640–7. PubMed Abstract | Publisher Full Text | Free Full Text
  • 128.  Friedberg JW, Mahadevan D, Cebula E, et al.: Phase II study of alisertib, a selective Aurora A kinase inhibitor, in relapsed and refractory aggressive B- and T-cell non-Hodgkin lymphomas. J Clin Oncol. 2014; 32(1): 44–50. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
  • 129.  Barr PM, Li H, Spier C, et al.: Phase II Intergroup Trial of Alisertib in Relapsed and Refractory Peripheral T-Cell Lymphoma and Transformed Mycosis Fungoides: SWOG 1108. J Clin Oncol. 2015; 33(21): 2399–404. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
  • 130.  O'Connor OA, Özcan M, Jacobsen ED, et al.: First Multicenter, Randomized Phase 3 Study in Patients (Pts) with Relapsed/Refractory (R/R) Peripheral T-Cell Lymphoma (PTCL): Alisertib (MLN8237) Versus Investigator's Choice. Annual Meeting of American Society of Hematology. Blood. 2015; 126(23): 341. Reference Source
  • 131.  Witzig TE, Tang H, Micallef IN, et al.: Multi-institutional phase 2 study of the farnesyltransferase inhibitor tipifarnib (R115777) in patients with relapsed and refractory lymphomas. Blood. 2011; 118(18): 4882–9. PubMed Abstract | Publisher Full Text | Free Full Text
  • 132.  Witzig T, Sokol L, Jacobsen E, et al.: Preliminary Results From An Open-Label, Phase II Study Of Tipifarnib In Relapsed Or Refractory Peripheral T-Cell Lymphoma. Hematol Oncol. 2017; 35(S2): 251–2. Publisher Full Text
  • 133.  Stuart SD, Schauble A, Gupta S, et al.: A strategically designed small molecule attacks alpha-ketoglutarate dehydrogenase in tumor cells through a redox process. Cancer Metab. 2014; 2(1): 4. PubMed Abstract | Publisher Full Text | Free Full Text
  • 134.  Pardee TS, Lee K, Luddy J, et al.: A phase I study of the first-in-class antimitochondrial metabolism agent, CPI-613, in patients with advanced hematologic malignancies. Clin Cancer Res. 2014; 20(20): 5255–64. PubMed Abstract | Publisher Full Text | Free Full Text
  • 135.  Lamar ZS, Isom S, Vaidya R, et al.: Phase I Dose-Escalation Study of Cpi-613, in Combination with Bendamustine, in Relapsed or Refractory T-Cell Non-Hodgkin Lymphoma. Annual Meeting of American Society of Hematology. Blood. 2016; 128(22): 4163. Reference Source

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Yi JH, Kim SJ and Kim WS. Recent advances in understanding and managing T-cell lymphoma [version 1; peer review: 2 approved]. F1000Research 2017, 6(F1000 Faculty Rev):2123 (https://doi.org/10.12688/f1000research.12573.1)
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Shigeru Chiba, Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan 
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Christian Gisselbrecht, Institut d'Hématologie, Hôpital Saint-Louis, Paris, France 
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Gisselbrecht C. Reviewer Report For: Recent advances in understanding and managing T-cell lymphoma [version 1; peer review: 2 approved]. F1000Research 2017, 6(F1000 Faculty Rev):2123 (https://doi.org/10.5256/f1000research.13616.r28593)
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    Alongside their report, reviewers assign a status to the article:
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