PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of f1000resSubmitAuthor GuidelinesAboutAdvisory PanelF1000ResearchView this article
 
Version 1. F1000Res. 2017; 6: 2123.
Published online 2017 December 12. doi:  10.12688/f1000research.12573.1
PMCID: PMC5728196

Recent advances in understanding and managing T-cell lymphoma

Jun Ho Yi, Supervision, Writing – Original Draft Preparation,1 Seok Jin Kim, Project Administration, Supervision,2 and Won Seog Kim, Supervision, Writing – Review & Editinga,2

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

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 revised 1. 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 rituximab 2, 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) cells 47 and have common genetic features, such as RHOA, TET2, DNMT3A, and IDH 811. 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 TBX21 12, 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 favorable 13, the five-year survival rate is comparable to that of ALK-positive ALC when DUSP22 rearrangements are found 14. After first being described in 1997 15, 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 course 16, 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 differences 1820. 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 disease 21. The course of this disease is known to be indolent, although some cases of transformation have been reported 22.

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 PTCLs 23, 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 outcomes 2527. Owing to the lack of efficacy of conventional CHOP, more intensive anthracycline-based regimens have been tried 2832; 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 patients 33, 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 PTCL 35. 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 survival 36. 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 arm 37. 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 + CHOP 123 II3057%/33%2-year PFS: 33%
2-year OS: 70%
Neutropenia: 80%
Thrombocytopenia: 60%
Bortezomib + CHOP 114 II4665%/9%2-year PFS: 37%
2-year OS: 52%
Neutropenia: 41%
Romidepsin + CHOP 65 Ib/II3751%/17%30-months PFS: 41%
30-months OS: 71%
Neutropenia: 89%
Thrombocytopenia: 78%
Belinostat + CHOP 100 Ib2372%/17%Not reportedNeutropenia: 26%
Anemia: 22%
Non-anthracycline combinations
Cyclophosphamide, etoposide, vincristine,
prednisone alternating with pralatrexate 80
II3352%/18%2-year PFS: 39%
2-year OS: 60%
Gemcitabine, etoposide, cisplatin,
methylprednisolone 35
II2623%/15%2-year PFS: 14%
2-year OS: 36%
Neutropenia: 45%
Anemia: 24%
Gemcitabine, cisplatin,
methylprednisolone 37
II4443%/not
reported
2-year PFS: 39%
2-year OS: 65%
Gemcitabine, cisplatin, prednisone,
thalidomide 111
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 PTCL 23, 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 performed 38. 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-14 39. 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%, respectively 40. 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 ASCT 41, 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 disease 38, 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 poor 43. 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 vedotinII 52 58 (ALCL)57%/29%1-year OS rate: 70%
4-year OS rate: 64%
5-year OS rate: 60%
Peripheral sensory neuropathy,
neutropenia, thrombocytopenia
II 58 35
(non-ALCL)
24%/18%Median PFS: 2.6 monthsPeripheral sensory neuropathy,
neutropenia, hyperkalemia
MogamulizumabII 64 3814%/19%Median PFS: 3.0 monthsLymphocytopenia, neutropenia
Anti-folates
PralatrexateII 76 11111%/18%Median PFS: 3.5 months
Median OS: 14.5 months
Neutropenia, thrombocytopenia,
mucositis
Histone deacetylase inhibitors
RomidepsinII 89 13115%/11%Median PFS: 4.0 months
Median OS: 11.3 months
Neutropenia, thrombocytopenia
Romidepsin + gemcitabineII 94 2015%/15%2-year PFS: 11%
2-year OS: 50%
Neutropenia, thrombocytopenia,
anemia
BelinostatII 98 12011%/15%Median PFS: 1.6 months
Median OS: 7.9 months
Neutropenia, fatigue
ChidamideII 102 8314%/15%Median PFS: 2.1 months
Median OS: 21.4 months
Neutropenia, thrombocytopenia
Immunomodulatory drugs
LenalidomideII 108 5411%/11%Median PFS: 1.9 monthsNeutropenia, thrombocytopenia,
pneumonia, gastrointestinal disorder
II 109 408%/18%Median PFS: 4 months
Median OS: 12 months
Neutropenia, pain, dyspnea
Inhibitors of PI3K/mTOR pathways
DuvelisibI 117 1513%/33%Median OS: 36.4 weeksHepatitis, rash, neutropenia
CopanlisibII 119 1714%/7%Not reportedHypertension, neutropenia,
hyperglycemia
EverolimusII 124 166%/38%Median PFS: 4.1 months
Median OS: 10.2 months
Neutropenia, thrombocytopenia,
anemia, hyperglycemia
Alternative agents
BendamustineII 125 6028%/22%Median PFS: 3.6 months
Median OS: 6.2 months
Neutropenia, thrombocytopenia,
infection
Bendamustine + carboplatin
+ dexamethasone
II 126 3030%/25%Median PFS: 4.8 monthsNeutropenia, thrombocytopenia,
anemia
AlisertibIII 130 12016%/17%Median PFS: 3.7 months
Median OS: 9.9 months
Neutropenia, thrombocytopenia,
anemia
TipifarnibII 132 180%/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 monotherapy 44 or as combination therapy with various backbones 4547. Although high CR rates were observed (36–54%), severe opportunistic infections caused concerns. Combinations of alemtuzumab with conventional three-weekly CHOP 48, two-weekly CHOP 49, four-weekly CHOP 50, and CHOEP-14 51 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 cycles 52. 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 treatment 53, 54. For PTCLs other than ALCL, the rate of CD30 positivity varies according to subtype and report 14, 5557. 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 alive 60. 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 cases 61 and in approximately 30–65% of patients with PTCLs 62, 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 weeks 64. 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 noted 65. 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 evasion 66, 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 cases 68 and that PD-L1 is frequently expressed in certain virus-associated lymphomas 69, 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 weeks 70. 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 anecdote 71, 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 weeks 73. 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 methionine 74.

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 mucositis 75. This toxicity was later found to be alleviated by the administration of vitamin B 12 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/m 2 for six out of seven weeks along with vitamin B 12 and folic acid 76. 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 cases 77.

Based on the synergism pralatrexate has shown in preclinical analyses 78, 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 PTCL 80. 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 included 81. 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/m 2) and bortezomib (1.3 mg/m 2) for three out of four weeks until progression 82. 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 proteins 83, 84. Various classes of HDACs with clinical significance are expressed in patients with PTCL 85, 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 trial 87, a phase II trial was carried out in 47 patients with rrPTCL 88. Romidepsin was administered in three out of four weeks with a starting dose of 14 mg/m 2, which could be escalated up to 17.5 mg/m 2 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 trial 89, a total of 131 patients with rrPTCL received romidepsin at a dose of 14 mg/m 2 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) responses 90. In the phase II part of the Japanese trial, 40 patients with rrPTCL received 14 mg/m 2 of romidepsin 91. 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 cycle 92. In a Korean pilot study, however, three out of five patients with NK/T-cell lymphoma experienced EBV reactivation after romidepsin treatment 93. This finding is consistent with the findings from the aforementioned two cases of EBV-associated lymphoproliferative disorder 88. 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 PTCL 65. 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/m 2 (days 1, 8, and 15) with gemcitabine at 800 mg/m 2 (days 1 and 15) up to six cycles, followed by romidepsin maintenance (at 14 mg/m 2), was given to 20 patients with rrPTCL 94. 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 group 95, and of the 10 patients with PTCL, five responded. In addition, when romidepsin was added to ICE 96, 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 CR 97. 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/m 2 for five days every three weeks 98. 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/m 2 for five days every three weeks was combined with CHOP for six cycles in 23 patients with untreated PTCL 100. 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 10 101. In a phase II trial, 83 patients with rrPTCL took 30 mg of chidamide twice weekly 102. 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 released 103. 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, respectively 104. In a relapsed or refractory setting, a combination of vorinostat, lenalidomide, and dexamethasone (40 mg once daily) was explored 105, but the outcomes were not remarkable.

Panobinostat is an orally administered pan-HDAC inhibitor. In a phase II study 106, 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/m 2. 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 mechanisms 107. Two trials have investigated single-agent lenalidomide for 21 out of 28 days in patients with rrPTCL 108, 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 unique 108 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 rrPTCL 110. 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 PTCL 111. 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 rrCTCL 112. Because a chemosensitization effect was expected 113, the efficacy of bortezomib was explored in combination with CHOP in patients with newly diagnosed PTCL/ENKTL/CTCL 114. 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 PTCL 115. 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 mTOR 116.

Duvelisib, a dual inhibitor of PI3Kγ and δ, was studied in a phase 1 trial in patients with hematologic malignancies 117. 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 lymphoma 118. 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 prognosis 120, 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 responded 121.

Activation of mTOR induces cell growth and survival in cancer, and especially in lymphoma, Myc activity is known to depend on the mTOR pathway 122. In a phase II study of 30 patients with untreated PTCL who received everolimus plus CHOP 123, 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 months 124.

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/m 2 for two consecutive days every three weeks for up to six cycles 125. 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 ASCT 126. 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 PTCL 127. Alisertib, a small-molecule inhibitor of aurora-A kinase, has demonstrated favorable anti-tumor efficacy against rrPTCL in two phase II trials 128, 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 gemcitabine 130. 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 choice 130. 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 weeks 131. 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 reported 132. 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 cells 133. In a phase I trial in patients with hematologic malignancies, the maximum tolerated dose was determined to be 2,940 mg/m 2, a major toxicity was renal failure 134. In another phase I trial in patients with relapsed or refractory T-cell lymphoma, bendamustine plus CPI-613 was administered 135. 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.

Notes

[version 1; referees: 2 approved]

Funding Statement

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

Notes

Editorial Note on the Review Process

F1000 Faculty Reviews are commissioned from members of the prestigious F1000 Faculty and are edited as a service to readers. In order to make these reviews as comprehensive and accessible as possible, the referees provide input before publication and only the final, revised version is published. The referees who approved the final version are listed with their names and affiliations but without their reports on earlier versions (any comments will already have been addressed in the published version).

The referees who approved this article are:

  • Shigeru Chiba, Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
    No competing interests were disclosed.
  • Christian Gisselbrecht, Institut d'Hématologie, Hôpital Saint-Louis, Paris, France
    No competing interests were disclosed.

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. 10.1182/blood-2016-01-643569 [PubMed] [Cross Ref]
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]
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]
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. 10.1182/blood.V99.2.627 [PubMed] [Cross Ref]
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 (T FH) cells. Blood. 2007;109(11):4952–63. 10.1182/blood-2006-10-055145 [PubMed] [Cross Ref]
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. 10.3324/haematol.2009.010991 [PubMed] [Cross Ref]
7. Lemonnier F, Couronné L, Parrens M, et al. : Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with T FH-like features and adverse clinical parameters. Blood. 2012;120(7):1466–9. 10.1182/blood-2012-02-408542 [PubMed] [Cross Ref]
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. 10.1038/ng.2916 [PubMed] [Cross Ref] 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. 10.1038/ng.2873 [PMC free article] [PubMed] [Cross Ref] 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. 10.1038/ng.2872 [PubMed] [Cross Ref] 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. 10.1182/blood-2011-11-391748 [PMC free article] [PubMed] [Cross Ref]
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. 10.1182/blood-2013-11-536359 [PubMed] [Cross Ref]
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. 10.1182/blood-2008-01-134270 [PubMed] [Cross Ref]
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. 10.1182/blood-2014-04-571091 [PubMed] [Cross Ref]
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]
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. 10.1200/JCO.2013.52.7911 [PMC free article] [PubMed] [Cross Ref]
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. 10.1093/annonc/mdv575 [PMC free article] [PubMed] [Cross Ref] 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. 10.1038/leu.2010.295 [PubMed] [Cross Ref]
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. 10.1038/leu.2013.41 [PubMed] [Cross Ref]
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. 10.1038/ncomms12602 [PMC free article] [PubMed] [Cross Ref] 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. 10.1182/blood-2013-07-512830 [PubMed] [Cross Ref]
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. 10.1371/journal.pone.0068343 [PMC free article] [PubMed] [Cross Ref]
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. 10.6004/jnccn.2016.0117 [PubMed] [Cross Ref] 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. 10.1093/annonc/mdv201 [PubMed] [Cross Ref]
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. 10.1093/annonc/mdh392 [PubMed] [Cross Ref]
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. 10.1200/JCO.2008.16.4558 [PubMed] [Cross Ref] 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. 10.5402/2011/623924 [PMC free article] [PubMed] [Cross Ref]
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. 10.1002/cncr.20999 [PubMed] [Cross Ref]
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]
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. 10.1111/j.1365-2141.2010.08329.x [PubMed] [Cross Ref]
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. 10.1182/blood-2003-02-0542 [PubMed] [Cross Ref]
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. 10.1111/j.1365-2141.2011.08634.x [PubMed] [Cross Ref]
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. 10.1182/blood-2003-06-2094 [PubMed] [Cross Ref]
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. 10.1182/blood-2003-06-2095 [PubMed] [Cross Ref]
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. 10.1002/cncr.27733 [PMC free article] [PubMed] [Cross Ref]
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. 10.1007/s00280-005-0136-y [PubMed] [Cross Ref]
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. 10.1002/hon.2437_63 [Cross Ref]
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. 10.1200/JCO.2008.17.4870 [PubMed] [Cross Ref]
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. 10.1200/JCO.2011.40.2719 [PubMed] [Cross Ref] 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. 10.1016/j.bbmt.2015.01.013 [PMC free article] [PubMed] [Cross Ref] 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. 10.1200/JCO.2012.44.7524 [PubMed] [Cross Ref] 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. 10.1182/blood-2003-10-3389 [PubMed] [Cross Ref]
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. 10.1093/annonc/mdn726 [PubMed] [Cross Ref]
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. 10.3109/10428190903580402 [PubMed] [Cross Ref]
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. 10.1200/JCO.2009.22.6688 [PMC free article] [PubMed] [Cross Ref]
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. 10.1007/s00280-007-0469-9 [PubMed] [Cross Ref]
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. 10.1093/annonc/mdq635 [PubMed] [Cross Ref]
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. 10.1182/blood-2007-02-074641 [PubMed] [Cross Ref]
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. 10.1007/s00277-013-1880-4 [PMC free article] [PubMed] [Cross Ref]
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. 10.1200/JCO.2011.38.0402 [PubMed] [Cross Ref]
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. 10.1182/blood-2010-09-310342 [PubMed] [Cross Ref]
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]
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. 10.1309/V561QTM6854W4WAV [PubMed] [Cross Ref]
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. 10.1182/blood-2013-12-542142 [PubMed] [Cross Ref]
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. 10.1200/JCO.2013.54.2456 [PMC free article] [PubMed] [Cross Ref]
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]
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. 10.1158/1078-0432.CCR-04-0371 [PubMed] [Cross Ref]
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]
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. 10.1200/JCO.2013.52.0924 [PubMed] [Cross Ref]
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. 10.1016/S2352-3026(15)00023-X [PubMed] [Cross Ref] 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. 10.1182/blood-2007-05-085159 [PubMed] [Cross Ref]
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. 10.1182/blood-2007-08-105395 [PubMed] [Cross Ref]
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. 10.1097/01.pas.0000209855.28282.ce [PMC free article] [PubMed] [Cross Ref]
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. 10.1158/1078-0432.CCR-13-0855 [PMC free article] [PubMed] [Cross Ref]
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. 10.1200/JCO.2015.65.9789 [PMC free article] [PubMed] [Cross Ref] 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. 10.1007/s00277-016-2764-1 [PubMed] [Cross Ref]
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. 10.1182/blood-2016-12-756841 [PubMed] [Cross Ref]
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. 10.1158/1078-0432.CCR-12-2251 [PubMed] [Cross Ref]
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. 10.1200/JCO.2008.20.8470 [PMC free article] [PubMed] [Cross Ref] 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. 10.1200/JCO.2010.29.9024 [PMC free article] [PubMed] [Cross Ref] 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. 10.1111/cas.13340 [PMC free article] [PubMed] [Cross Ref] 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. 10.1158/1078-0432.CCR-05-0331 [PubMed] [Cross Ref]
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. 10.1158/1078-0432.CCR-10-0671 [PubMed] [Cross Ref]
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. 10.1111/bjh.13855 [PMC free article] [PubMed] [Cross Ref] 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. 10.3346/jkms.2016.31.7.1160 [PMC free article] [PubMed] [Cross Ref] 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. 10.1093/jnci/92.15.1210 [PubMed] [Cross Ref]
84. Bolden JE, Peart MJ, Johnstone RW.: Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov. 2006;5(9):769–84. 10.1038/nrd2133 [PubMed] [Cross Ref]
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. 10.1111/j.1365-2559.2009.03290.x [PubMed] [Cross Ref]
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. 10.1111/j.1365-2141.2009.07887.x [PMC free article] [PubMed] [Cross Ref]
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. 10.1182/blood.V98.9.2865 [PubMed] [Cross Ref]
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. 10.1182/blood-2010-10-312603 [PubMed] [Cross Ref]
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. 10.1200/JCO.2011.37.4223 [PubMed] [Cross Ref] 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. 10.1186/1756-8722-7-11 [PMC free article] [PubMed] [Cross Ref]
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. 10.1007/s12185-017-2286-1 [PubMed] [Cross Ref] 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. 10.1002/ijc.29698 [PubMed] [Cross Ref] 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. 10.1093/annonc/mdv596 [PubMed] [Cross Ref]
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. 10.1186/s13045-016-0266-1 [PMC free article] [PubMed] [Cross Ref] 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. 10.1111/bjh.13222 [PubMed] [Cross Ref] 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. 10.1200/JCO.2014.59.2782 [PMC free article] [PubMed] [Cross Ref] 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. 10.1007/s00280-011-1766-x [PubMed] [Cross Ref]
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. 10.1093/annonc/mdv237 [PubMed] [Cross Ref] 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. 10.1186/s13045-017-0439-6 [PMC free article] [PubMed] [Cross Ref] 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. 10.1111/bjh.12326 [PubMed] [Cross Ref]
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. 10.1007/s00277-014-2009-0 [PubMed] [Cross Ref]
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 [PubMed]
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. 10.1182/blood-2014-11-567792 [PubMed] [Cross Ref]
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. 10.1016/j.ejca.2013.04.029 [PubMed] [Cross Ref]
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. 10.1002/cncr.29103 [PubMed] [Cross Ref] 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. 10.1111/bjh.14763 [PubMed] [Cross Ref] 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. 10.1200/JCO.2007.11.4207 [PubMed] [Cross Ref]
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. 10.1038/sj.onc.1204168 [PubMed] [Cross Ref]
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. 10.1016/j.ejca.2012.06.003 [PubMed] [Cross Ref]
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. 10.1038/nrd2926 [PMC free article] [PubMed] [Cross Ref]
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 [PubMed]
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 10.1002/hon.2439_191 [Cross Ref]
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. 10.1093/annonc/mdx289 [PubMed] [Cross Ref] 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]
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. 10.1111/bjh.13603 [PMC free article] [PubMed] [Cross Ref] 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. 10.1073/pnas.1310230110 [PubMed] [Cross Ref]
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. 10.1093/annonc/mdv624 [PubMed] [Cross Ref]
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. 10.1182/blood-2015-02-629543 [PubMed] [Cross Ref] 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. 10.1200/JCO.2012.43.7285 [PubMed] [Cross Ref]
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. 10.1002/hon.2439_161 [Cross Ref]
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. 10.1038/modpathol.2012.211 [PMC free article] [PubMed] [Cross Ref]
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. 10.1200/JCO.2012.46.8793 [PMC free article] [PubMed] [Cross Ref] 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. 10.1200/JCO.2014.60.6327 [PMC free article] [PubMed] [Cross Ref] 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. 10.1182/blood-2011-02-334904 [PubMed] [Cross Ref]
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. 10.1002/hon.2438_115 [Cross Ref]
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. 10.1186/2049-3002-2-4 [PMC free article] [PubMed] [Cross Ref]
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. 10.1158/1078-0432.CCR-14-1019 [PMC free article] [PubMed] [Cross Ref]
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

Articles from F1000Research are provided here courtesy of F1000 Research Ltd