Abstract

Peripheral T-cell lymphoma, not otherwise specified, is a broad category of biologically and clinically heterogeneous diseases that cannot be further classified into any other of the existing entities defined by the World Health Organization classification. Anthracycline-containing regimens, namely cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), nowadays represent the standard first-line treatment; for patients who achieve a satisfactory response, a consolidation by means of autologous stem cell transplantation may offer a greater chance of long-term survival. Several patients, however, display treatment refractoriness or relapse soon after obtaining a response, and just a few of them are suitable transplant candidates. This is why several new agents, with innovative mechanisms of action, have been investigated in this context: pralatrexate, romidepsin, belinostat, and brentuximab vedotin have been approved for relapsed and refractory peripheral T-cell lymphomas based on their activity, although they do not significantly affect survival rates. The incorporation of such new drugs within a CHOP backbone is under investigation to enhance response rates, allow a higher proportion of patients to be transplanted in remission, and prolong survival.

Introduction

Peripheral T-cell non-Hodgkin lymphoma (PTCL), not otherwise specified (NOS), is the most common PTCL subtype, accounting for at least 25% of PTCL.1,2  It mostly affects adult patients, with a median age at presentation of 60 years and male predominance. According to data from the International T-cell Lymphoma Project,2  the disease is equally spread in Europe and North America, whereas it shows a slightly lower prevalence in Asia (34.3%, 34.4%, and 22.4% of PTCL, respectively). Nodal involvement is prevalent at diagnosis, although any organ can be affected, including bone marrow (22%), liver, spleen, and skin, in combination with nodal disease. Advanced stage at presentation is common (∼70% of cases), with almost two-thirds of patients presenting with an intermediate to high International Prognostic Index (IPI).3 

New classification issues and molecular signature

PTCL-NOS is diagnosed on an exclusion basis as a disease whose features are not consistent with any of the other PTCL subtypes defined by the World Health Organization classification.1  With current immunophenotypic and molecular markers, in fact, about 30% to 50% of PTCL cases are not further classifiable and are categorized as PTCL-NOS.2  As a consequence, this disease is heterogeneous and displays a broad cytological spectrum and a multiplicity of molecular aspects.4-6 

Gene expression profiling has improved the diagnosis of PTCL, which allows a better classification within well-specified subgroups4-7 : about 15% of pathologically diagnosed PTCL-NOS can be reclassified as angioimmunoblastic T-cell lymphoma (AITL),8  whereas in nearly 10% of cases, a correct diagnosis of anaplastic large cell lymphoma (ALCL) or extranodal natural killer/T-cell lymphoma can be ruled out.7  Moreover, genetic studies have shown that some recurrent genetic abnormalities of TET2, IDH2, DNMT3A, RHOA, and CD28 have been observed in cases of PTCL-NOS, and manifest a T-follicular helper phenotype, as happens with AITL.9-11  For this reason, the former follicular variant of PTCL-NOS has been moved to the new T-follicular helper-lymphoma category in the 2016 WHO classification.12  Recurrent gene fusions of VAV1, which encodes a critical component of the T-cell receptor signaling, have been recently described in a relevant proportion of PTCL-NOS and ALCL,13  along with rearrangements of ITK with genes such as SYK, FER, and ERBB4; this suggests their possible role in regulating cell growth and in ultimately driving T-cell lymphomagenesis14  as well as representing potential targets for therapy to be extensively exploited in rationally designed clinical trials. TP63 rearrangements have also been recurrently found in PTCL-NOS and ALCL characterized by high proliferation indices and more severe prognosis.13,15 

Significant improvements have been made in delineating specific biological and prognostic subgroups within the PTCL-NOS spectrum. Iqbal et al have demonstrated that 2 major molecular clusters can be identified7 : 1 group shows a high expression of GATA3 and an enrichment of gene signatures related to cell proliferation (MYC), mammalian target of rapamycin, and β-catenin; the other group significantly expresses TBX21 (T-bet) and is enriched of interferon-γ and NF-κB–induced gene signatures.7  Moreover, a subset of cases within the second group demonstrates enhanced expression of transcripts associated with cytotoxic T cells, probably representing the cytotoxic variant identified previously.5  The expression of GATA3 substantially excludes the TBX21 signature, and vice versa, thus permitting a clear distinction between the 2 subgroups. Importantly, GATA3 expression confers a poor prognosis, with a 5-year overall survival (OS) of 19%,7,16  whereas cases with a TBX21 signature display more favorable outcomes (5-year OS, 38%).7 

Dissimilarities also exist according to the expression of the surface CD30 antigen.17,18  CD30+-PTCL-NOS show a significant downregulation of genes involved in T-cell differentiation/activation (such as surface antigens CD28, CD52, and CD69 and the transcription factor NFATc2) and T-cell receptor signal transduction (eg, tyrosin kinases Lck, Fyn, and Itk), whereas they display enhanced expression of transcription factors such as JunB and MUM1/IRF4. The expression of these genes is similar between CD30+-PTCL-NOS and ALK-ALCL, but a striking difference exists between the CD30+ and CD30 forms, with the latter having just an opposite expression pattern.19  In other words, CD30+-PTCL-NOS and ALK-ALCL are mostly intermingled with one another, reflecting similarities in terms of morphological appearance and gene expression. Conversely, CD30-PTCL-NOS are not only molecularly divergent, but also show a different clinical behavior: their OS and progression-free survival (PFS) rates (24 and 10.5 months, respectively) are clearly worse than what is seen in CD30+-PTCL-NOS and ALCL (approximately 60%), although without statistical significance.19  The real prognostic significance of CD30 expression, however, still remains to be confirmed.

Despite the segregation of PTCL-NOS on the basis of the differential GATA3/TBX21 signature or in terms of CD30 expression appearing clinically meaningful, the diagnostic refinement is not part of routine practice and has no impact on the decision of first-line treatment.

Prognostic scores

Several prognostic scores have been proposed to provide a clinical stratification of PTCL-NOS patients20-23  (Table 1). The IPI, specifically designed for aggressive non-Hodgkin lymphoma, is also valid in T-cell neoplasms and can be determined using clinically derived variables.20  It is significantly associated with treatment outcomes, which appear better for lower scores: patients with a low score (0/1 prognostic factors) have a 36% 5-year failure-free survival (FFS) and a 50% 5-year OS, in contrast with those with a high score (4/5 prognostic factors), whose 5-year overall survival is only 11%, with 9% FFS.24 

Table 1.

Variables used in the calculation of relevant prognostic scores

IPI20 PIT21 m-PIT22 ITCLP23 
Age (>60 y) ● ● ● ● 
ECOG (>1) ● ● ● ● 
LDH (elevated values) ● ● ●  
Ann Arbor stage (III-IV) ●    
Extranodal involvement (≥2 sites) ●    
Bone marrow involvement  ●   
Platelet count (<150 000/mmc)    ● 
Ki-67 (≥80%)   ●  
IPI20 PIT21 m-PIT22 ITCLP23 
Age (>60 y) ● ● ● ● 
ECOG (>1) ● ● ● ● 
LDH (elevated values) ● ● ●  
Ann Arbor stage (III-IV) ●    
Extranodal involvement (≥2 sites) ●    
Bone marrow involvement  ●   
Platelet count (<150 000/mmc)    ● 
Ki-67 (≥80%)   ●  

To better define the clinical outcomes of PTCL-NOS cases, newer scores have been specifically built up: the Prognostic Index for PTCL-NOS (PIT)21  and the modified PIT (m-PIT).22  They share age (>60 years), Eastern Cooperative Oncology Group (ECOG) performance status (>1), and lactate dehydrogenase (LDH) elevation with IPI; PIT also takes into account bone marrow infiltration, whereas m-PIT integrates the expression of the proliferation-associated protein Ki-67. A fourth prognostic index derived from the International T-cell Lymphoma Project (ITCLP) indicates age (>60 years), ECOG (>1), and thrombocytopenia (<150 000/mmc) as the 3 most relevant parameters in the stratification of PTCL-NOS patients.23  Importantly, all of these prognostic scores have been validated in subpopulations treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), or at least an anthracycline-containing regimen. The 4 scores divide PTCL-NOS patients in 3 (m-PIT, ITCLP) or 4 (IPI, PIT) prognostic categories: the lower risk group, whichever score is used (score 0/1 for IPI and m-PIT, score 0 for PIT and ITCLP), emerges as a clearly separated category and shows better outcomes than all the other risk groups20-27  (Table 2). Whether the approach to lower risk patients should be more conservative, however, is matter of discussion, because at least 60% to 70% of these patients are likely to relapse within the first 5 years.

Table 2.

Comparison of IPI- and PIT-calculated survival outcomes in 4 PTCL-NOS case series

IndexScoreGallamini et al, 200421 Weisenburger et al, 201124 Ellin et al, 201425 Xu et al, 201526 
5-y OS, %5-y OS, %5-y FFS, %5-y OS, %5-y OS, %5-y PFS, %
IPI20  Low 0/1 59 50 36 58 48 43 
Low-intermediate 46 33 18 27* 38 19 
Intermediate-high 40 16 15 13 
High 4/5 18 11 15 
PIT21  Group 1 62 50 34 71 56 33 
Group 2 53 40 22 38 40 21 
Group 3 33 22 13 25 25 14 
Group 4 3/4 18 11 18 NR 
IndexScoreGallamini et al, 200421 Weisenburger et al, 201124 Ellin et al, 201425 Xu et al, 201526 
5-y OS, %5-y OS, %5-y FFS, %5-y OS, %5-y OS, %5-y PFS, %
IPI20  Low 0/1 59 50 36 58 48 43 
Low-intermediate 46 33 18 27* 38 19 
Intermediate-high 40 16 15 13 
High 4/5 18 11 15 
PIT21  Group 1 62 50 34 71 56 33 
Group 2 53 40 22 38 40 21 
Group 3 33 22 13 25 25 14 
Group 4 3/4 18 11 18 NR 
*

Low-intermediate and high-intermediate risk patients according to IPI are grouped together as intermediate risk patients.

The value of PET scans in managing the disease

18F-fluorodeoxyglucose avidity is less predictable in T-cell lymphomas than in B-cell counterparts, but it is known that up to 90% of nodal PTCL shows 18F-fluorodeoxyglucose–avid lesions,28  and both nodal and extranodal involvement can be detected upon positron emission tomography (PET). At present, no recommendations exist regarding routine use of PET scan during disease staging and restaging. It is known from published data that results from PET scans are able to change the disease stage in nearly 5% of patients at diagnosis,29  compared with computed tomography scans, but this change does not translate into any treatment alteration because systemic chemotherapy in nodal PTCL is generally used regardless of tumor extent. However, a more accurate description of disease extent at diagnosis, in particular in terms of extranodal presentation, may prove useful in response assessment and follow-up evaluation, and may also convey some prognostic information, given that the involvement of liver or lung has proven to be related to a possible worse outcome.30 

PET positivity found at the end of induction treatment30,31  and in patients who have received autologous stem cell transplantation (autoSCT) is a strong predictor of reduced survival,32  and this seems particularly true for PTCL-NOS and AITL patients. On the contrary, uncertainty still exists on the role of interim PET evaluation during induction treatment. Some published experiences document that a negative interim scan (described in terms of the International Harmonization Project or applying the Deauville 5-point scale) has a favorable impact on OS29,33  and perhaps on PFS,34  possibly because PET-negative patients were more likely to receive consolidation therapy, which contributed to their better survival rates. On the other hand, other studies show a lack of any prognostic value.30 

First-line treatment

Anthracycline-based induction regimens

The main goal of first-line treatment should be to achieve deep remission and long-term control of the disease, if not a cure. Anthracycline-based regimens are considered the current standard of care in induction treatment of PTCL patients, as demonstrated in several reported experiences in which the CHOP combination was adopted in a proportion of patients variable from 60% to 85%.2,24,35-37  A meta-analysis by Abouyabis et al showed that anthracycline-based regimens used as an induction strategy in PTCL-NOS patients could induce a complete response (CR) in 17% to 70% of patients, according to different published series,38  but with a high rate of disease relapse or progression, yielding a 5-year OS of 32% to 45%.38  The ITCLP failed to demonstrate any statistically significant survival advantage in terms of OS for PTCL-NOS patients receiving anthracyclines during induction over those who were treated with anthracycline-free regimens:2  patients obtained 5-year FFS and OS of just 20% and 32%, respectively.24  The same trend was evident in a previously published report from the British Columbia Cancer Agency,35  in which at least 75% of PTCL-NOS patients received CHOP chemotherapy and obtained a CR in 64% of cases, but with a 5-year PFS of only 29%. On the contrary, a more recent experience from Mayo Clinic and the University of Michigan showed superior outcomes in 326 patients with PTCL treated with anthracyclines during induction compared with those who did not received anthracyclines: the difference remained significant when PTCL-NOS and AITL cases (191 patients) were extrapolated (median PFS and OS of 10 and 18 months for anthracycline-treated patients vs <2 months in non–anthracycline-treated individuals) and when intermediate- to high-risk IPI cases were analyzed. Moreover, anthracycline-treated patients were more prone to receive bone marrow transplantation, either in first or second remission.39 

More intensive chemotherapy regimens have not proven to be more effective than CHOP in historical controls38 ; moreover, in a phase 3 randomized study by Simon et al, an alternative induction schedule including etoposide, ifosfamide, and cisplatin, alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine did not show any superiority in terms of event-free survival (EFS) over CHOP (given every 21 days), thus confirming CHOP as the reference regimen for PTCL patients.40 

The role of adding etoposide to CHOP (CHOEP) during induction was investigated in depth by the German High-Grade Non-Hodgkin Lymphoma Study Group41 : CHOEP, given either every 14 or 21 days, improved response and EFS rates in young patients with normal LDH levels (3-year EFS was 70.5% after CHOEP and 51.0% after CHOP, P = .004), although 3-year OS did not significantly differ between the 2 groups (81.3% for CHOEP vs 75.2% for CHOP, P = .285). More specifically, PTCL-NOS patients treated with CHOEP (22% of the patients) had a 3-year EFS and OS of 41.1% and 53.9%, respectively. Of note, attempts to improve outcomes in younger patients by escalating doses of any of the drugs included in CHOEP have failed. In addition, CHOEP failed to enhance clinical outcomes in patients older than 60 years, for whom CHOP should remain the standard first-line approach.

Non–anthracycline-based induction regimens

Besides CHOP, anthracycline-free combinations have also been tested as induction strategies in PTCL. The cisplatin, etoposide, gemcitabine, and methylprednisolone regimen was conceived to use agents not effluxed by multidrug-resistance glycoprotein, whose expression confers chemotherapy resistance.42  In 26 patients treated first-line, the overall response rate (ORR) was 38% and the CR rate was 23%, which translated into a disappointing 2-year PFS of 14% and OS of 36%. Another gemcitabine-containing regimen—gemcitabine, cisplatin, and methylprednisolone—previously tested in 16 relapsed or refractory PTCL patients,43  is now being evaluated in a randomized phase 2 trial, which involves CHOP chemotherapy as the control arm (#NCT01719835).

Frontline consolidation with autologous transplantation

Given the short duration of remission and the high risk of relapse of PTCL patients responding to first-line treatment, frontline consolidation with autoSCT has been considered a valid therapeutic opportunity for patients achieving at least a partial response to induction.

Two prospective Italian phase 2 studies, reported together by Corradini et al and involving 62 patients with advanced-stage PTCL, demonstrated a high CR rate (89%) after frontline autoSCT, with a 12-year OS, disease-free survival, and EFS of 34%, 55%, and 30%, respectively. OS and EFS projections at 12 years obtained for the subgroup of PTCL-NOS patients (45% of the total) were 37% and 25%, respectively.44  More disappointing results emerged from a Spanish study that involved 41 patients with PTCL treated upfront with intensified CHOP alternated with an etoposide, cisplatin, cytarabine, and prednisone regimen: 51% of the 24 transplanted patients were in CR after autoSCT, with 4-year OS and PFS of 39% and 30%, respectively, for the intention-to-treat population.45  This can be partly explained by the fact that this study specifically excluded ALK+-ALCL patients, whereas the previously reported Italian studies did not. Reimer et al reported the results of a prospective multicenter trial in which 83 patients (32 with PTCL-NOS) were treated with 6 to 8 CHOP cycles followed by mobilizing chemotherapy and total body irradiation + cyclophosphamide myeloablative therapy, with the rescue of autologous stem cells. Fifty-five patients were transplanted, with an intention-to-treat CR rate of 58% and an estimated 3-year OS of 48%, which increased to 71% if only the cohort of transplanted patients was considered.46  ALK+-ALCL patients were again excluded from the study. The Nordic Lymphoma Group applied a CHOEP induction strategy (given every 14 days), although omitting etoposide in patients older than age 60 years, in 160 PTCL patients (excluding ALK+ALCL).47  The fifth or sixth cycle was used as a mobilizing therapy, whereas the upfront autoSCT was conditioned by carmustine, etoposide, cytarabine, and melphalan (or high-dose cyclophosphamide). The reported CR rate was 51%; the 5-year OS and PFS were 51% and 44% for the entire patient population, respectively; for PTCL-NOS patients, 5-year OS and PFS were 47% and 38%, respectively. No differences in OS and PFS were noted between CHOEP- and CHOP-treated subgroups, depending on patients’ age.

Taken together, these studies suggest that autoSCT consolidation seems to offer a greater chance of long-term survival in PTCL patients. Nevertheless, a substantial proportion of patients (16% to 41%) had evidence of progressive disease during induction or immediately before transplantation,44-47  thus precluding an effective consolidation in many instances. Moreover, no randomized trials have specifically clarified whether upfront autoSCT should be regarded as superior to conventional chemotherapy.36 

New drugs in relapsed disease

As previously discussed, durable remissions are uncommon with anthracycline-containing regimens, particularly in patients with high-risk disease; moreover, autoSCT cannot be performed in a significant proportion of patients, mainly because they do not achieve an adequate response or progress early. PTCL patients with recurrent disease display a dismal prognosis; their therapy represents an unmet medical need because the best treatment strategy is yet to be determined. A study in 153 relapsed and refractory PTCL patients, including 79 with PTCL-NOS, who were not candidates for autoSCT, documented a median OS and PFS after relapse of 5.5 and 3.1 months, respectively, which were marginally better for those who could receive chemotherapy at relapse (6.5 and 3.7 months, respectively; 6.5 and 3.8 months for PTCL-NOS).48 

Combination chemotherapy (ifosfamide-, platin-, or cytarabine-containing regimens) is sometimes used in younger and fitter patients, mostly as a bridge to autoSCT or allogeneic transplantation (alloSCT). However, responses are rarely seen in more than half of cases, response duration is short, and CR is occasional.49  Gemcitabine, used as single agent in older and more vulnerable patients, has shown evidence of efficacy in PTCL-NOS patients who obtained a 55% ORR and a 30% CR rate.50 

Four next-generation drugs (pralatrexate, romidepsin, brentuximab vedotin, and belinostat) have recently been approved by the Food and Drug Administration for the treatment of relapsed and refractory PTCL. Approvals were based on response rates alone because none of these drugs has shown an increased OS; for this reason, European approvals of both pralatrexate and romidepsin have been rejected because of a lack of evident clinical benefit. Belinostat is not licensed in Europe, although it has been granted orphan designation status by the European Medicines agency. Brentuximab vedotin is solely approved for the treatment of relapsed or refractory systemic ALCL.

Given the overall rarity of each histologic subtype, it is important to remember that clinical trials specifically involving PTCL-NOS patients are lacking: outcomes obtained with new drugs will therefore be discussed for all the disease subgroups considered in each study. Data on PTCL-NOS will be presented separately, when available (Table 3).

Table 3.

Selected experiences with approved single-agents and off-label compounds in PTCL patients, including PTCL-NOS

TreatmentReferenceNo. of patientsORR, %CR, %Median OS, moMedian PFS, moPTCL-NOS, N (%)PTCL-NOS ORR, %Toxicity*
Pralatrexate 53 111 29 11 14.5 3.5 59 (53) 32 Mucositis, thrombocytopenia, nausea, fatigue, anemia, constipation, pyrexia, anemia, edema, cough, epistaxis, vomiting, neutropenia, diarrhea 
Romidepsin 55 47 38 18 NA NA 27 (57) 41 (19)§ ECG T-wave changes, nausea, fatigue, thrombocytopenia, leukopenia, hypocalcemia 
56 130 25 15 NA 4.0 69 (53) 29 (14)§ Nausea, asthenia/fatigue, thrombocytopenia, vomiting, diarrhea, pyrexia, neutropenia, constipation, anorexia, anemia, dysgeusia 
Bendamustine 66 58 50 28 6.3 3.6 23 (40) 41 Neutropenia, thrombocytopenia, infections 
Lenalidomide 68 10 30 30 NA NA 10 (100) 30 (30)§ Neutropenia 
69 54 22 11 NA 2.5 20 (37) 20 Thrombocytopenia 
70 39|| 26 12.0 4.0 14 (36) 43 (14)§ Pain, fatigue, constipation, rash, diarrhea, anorexia, edema, nausea, anemia, dizziness, dyspnea, infection, insomnia, muscle weakness, thrombocytopenia, cough, pruritus 
Brentuximab vedotin 62 34 42 24 NA 2.6 21 (62) 33 (14)§ Peripheral neuropathy, fatigue, leukopenia, neutropenia, thrombocytopenia, anemia, nausea, anorexia 
Belinostat 65 129 23 7.9 1.6 77 (64) 23 Nausea, fatigue, pyrexia, vomiting, constipation, diarrhea, dyspnea, rash, peripheral edema 
Alisertib 73 37 24 8.0 3.0 13 (35) 31 (8)§ Anemia, thrombocytopenia, fatigue, neutropenia, leucopenia, lymphopenia, alopecia, mucositis 
TreatmentReferenceNo. of patientsORR, %CR, %Median OS, moMedian PFS, moPTCL-NOS, N (%)PTCL-NOS ORR, %Toxicity*
Pralatrexate 53 111 29 11 14.5 3.5 59 (53) 32 Mucositis, thrombocytopenia, nausea, fatigue, anemia, constipation, pyrexia, anemia, edema, cough, epistaxis, vomiting, neutropenia, diarrhea 
Romidepsin 55 47 38 18 NA NA 27 (57) 41 (19)§ ECG T-wave changes, nausea, fatigue, thrombocytopenia, leukopenia, hypocalcemia 
56 130 25 15 NA 4.0 69 (53) 29 (14)§ Nausea, asthenia/fatigue, thrombocytopenia, vomiting, diarrhea, pyrexia, neutropenia, constipation, anorexia, anemia, dysgeusia 
Bendamustine 66 58 50 28 6.3 3.6 23 (40) 41 Neutropenia, thrombocytopenia, infections 
Lenalidomide 68 10 30 30 NA NA 10 (100) 30 (30)§ Neutropenia 
69 54 22 11 NA 2.5 20 (37) 20 Thrombocytopenia 
70 39|| 26 12.0 4.0 14 (36) 43 (14)§ Pain, fatigue, constipation, rash, diarrhea, anorexia, edema, nausea, anemia, dizziness, dyspnea, infection, insomnia, muscle weakness, thrombocytopenia, cough, pruritus 
Brentuximab vedotin 62 34 42 24 NA 2.6 21 (62) 33 (14)§ Peripheral neuropathy, fatigue, leukopenia, neutropenia, thrombocytopenia, anemia, nausea, anorexia 
Belinostat 65 129 23 7.9 1.6 77 (64) 23 Nausea, fatigue, pyrexia, vomiting, constipation, diarrhea, dyspnea, rash, peripheral edema 
Alisertib 73 37 24 8.0 3.0 13 (35) 31 (8)§ Anemia, thrombocytopenia, fatigue, neutropenia, leucopenia, lymphopenia, alopecia, mucositis 

ECG, electrocardiogram; NA, not assessed.

*

Toxic effects demonstrated in at least 20% of patients.

Drug has received a Food and Drug Administration approval in patients with relapsed and refractory peripheral T-cell lymphoma.

OS/PFS evaluation was not an endpoint of the study.

§

Figures in parentheses indicate the percentage of patients with PTCL-NOS obtaining a CR.

||

Includes 8 previously untreated patients not eligible for combination chemotherapy and 2 patients with lymphoblastic T-cell lymphoma.

Indicates that the drug has received a Food and Drug Administration approval in patients with CD30+ relapsed or refractory ALCL.

Pralatrexate

Pralatrexate is an IV antifolate agent with high affinity for the reduced folate carrier-1, which is responsible for its internalization; it also displays high affinity for folylpolyglutamate synthase, which causes its polyglutamylation and retention within the cytoplasm, minimizing extrusion via cell membrane efflux pumps. Intracytoplasmic pralatrexate inhibits dihydrofolate reductase and thymidylate synthase, thus disrupting the DNA and RNA synthesis required for cell proliferation.51  An early experience in patients with relapsed B- and T-cell malignancies indicated higher ORR rates in T-cell neoplasms (54% vs 31% for patients with B-cell lymphomas) and established its tolerability and efficacy on a weekly schedule.52  In the phase 2, single-arm Pralatrexate in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma (PROPEL) study,53  which involved 115 patients (111 received at least 1 dose) with relapsed or refractory PTCL, pralatrexate was administered as an IV bolus over 3 to 5 minutes at 30 mg/m2 per week for 6 weeks, followed by 1 week of rest, until progressive disease or unacceptable toxicity. More than half of the enrolled patients were affected by PTCL-NOS, although all the most frequent subtypes were represented. The ORR was 29%, including 11% of patients with CR and 18% with PR; 32% of patients with PTCL-NOS responded. Nineteen percent of patients who had never achieved a response to any prior conventional therapy responded to pralatrexate, indicating the ability of this drug to overcome resistance. ORR increased to 35% among those who received only 1 prior systemic treatment, suggesting that the response rate might be better if this agent was used earlier in the course of the disease. The median PFS for the entire population was 3.5 months, with a median OS of 14.5 months. Mucositis was the most relevant adverse event, which determined dose reductions in 23% of patients and caused withdrawal from treatment in 6% of cases.

Romidepsin

Romidepsin is a potent inhibitor of class 1 histone deacetylase (HDAC), given by IV, that inhibits gene transcription by interfering with the acetylation pattern of histone lysine residues, which in turns regulates the structure of chromatin. The mechanism of action is complex and not fully understood, but it ultimately results in cell growth inhibition, cell-cycle regulation, and apoptosis induction.54  It was first approved by the Food and Drug Administration in 2009 for the treatment of patients with cutaneous T-cell lymphoma following at least 1 systemic treatment; its activity was also demonstrated in PTCL.55  A pivotal, open-label, phase 2 study in 130 relapsed or refractory PTCL patients, among which there were 69 PTCL-NOS cases, demonstrated an ORR of 25%, with 19% CR and with 29% of patients responding despite being refractory to their most recent prior systemic therapy.56  Twenty-nine percent of PTCL-NOS patients responded, obtaining a CR in 14% of cases. Responses were seen across all the most frequent histologies, although these were lacking in patients with rarer disease entities. The median PFS was 4 months for the entire cohort of patients, increasing to 18 months for patients in CR, and OS was 11.3 months.57  As with other HDAC inhibitors, side effects associated with romidepsin are predominantly hematologic, including neutropenia, lymphopenia, thrombocytopenia, and anemia. Infections were commonly reported (55%), including upper respiratory tract and urinary infections, pneumonia, and sepsis, mostly in concomitance with reduced white blood cell counts. Electrocardiographic changes have also been reported, but were not clinically relevant for patients without preexisting cardiac abnormalities.58 

Given its efficacy as single agent, the role of romidepsin is now being explored in combination with conventional chemotherapy (gemcitabine,59  ifosfamide-containing regimens60 ), lenalidomide (#NCT01755975), pralatrexate (#NCT01947140), and azacytidine (#NCT01998035) in the setting of relapsed and refractory PTCL.

Brentuximab vedotin

Brentuximab vedotin is an anti-CD30 chimeric antibody conjugated to a microtubule-disrupting agent (monomethyl auristatin E) released by proteolytic cleavage once the antibody has bound to the surface antigen and has been internalized: monomethyl auristatin E blocks tubulin polymerization and alters the microtubule network within the cell, thus inducing cell-cycle blockade and cell death. Its role in relapsed and refractory systemic ALCL patients is discussed elsewhere.61  Given that roughly 20% to 25% of PTCL-NOS express CD30 in at least 50% of tumor cells,17,18  the use of brentuximab vedotin seems rational in this category of patients. In a phase 2 study published by Horwitz et al,62  35 patients with mature T-cell lymphoma with variable CD30 expression, among which were 22 PTCL-NOS patients, were treated with brentuximab vedotin at the dose of 1.8 mg/kg every 3 weeks. Responses were seen in 41% of cases, including 33% of patients with PTCL-NOS (14% were CR), without any apparent correlation between CD30 expression and depth of response (responses were also seen in cases of undetectable CD30 upon centralized pathological review). More recent data from the French named patient program experience in 56 patients with T-cell lymphomas, 11 of whom had PTCL-NOS, confirmed a clinical response in 27% of PTCL-NOS patients, with CR obtained in just 18% of cases.63  Different from the previously published experience,62  this paper indicates that a possible correlation between CD30 expression and response may exist: although the relationship between ORR and survival is influenced by histology, better responses to brentuximab vedotin were seen in those who displayed a higher CD30 expression, as documented by their better outcomes.63 

Belinostat

Belinostat is a hydroxamic acid-derived pan-HDAC inhibitor acting on all zinc-dependent HDAC enzymes. An early phase 2 experience demonstrated an ORR of 25% in pretreated PTCL patients, along with a favorable toxicity profile.64  The pivotal Belinostat in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma (BELIEF) trial in patients with relapsed or refractory PTCL involved 129 patients, more than half of which were affected by PTCL-NOS.65  Belinostat was IV-administered at the dose of 1000 mg/m2 on days 1 through 5 every 3 weeks; treatment was continued until death or unacceptable toxicity. Meaningful responses were seen in 16% of patients refractory to their last prior systemic treatment and, notably, in 23% of patients with PTCL-NOS. Median PFS was only 1.6 months, however, and the median OS was 7.9 months. In terms of safety, the most relevant adverse events observed within the study were nausea, fatigue, pyrexia, and anemia and thrombocytopenia.

Investigational and off-label therapies

Bendamustine, lenalidomide, and alisertib are 3 agents displaying relevant activity in PTCL-NOS patients.

Bendamustine has been evaluated at the dose of 120 mg/m2 (IV-administered on days 1-2 every 3 weeks) in the phase 2 Bendamustine in Patients With Refractory or Relapsed T-cell Lymphoma (BENTLY) trial of 60 patients with relapsed or refractory PTCL, including 23 patients with PTCL-NOS.66  Responses were seen across multiple histologies, including 41% ORR in PTCL-NOS, but their duration was short (3.5 months), lasting more than 1 year in only 7% of patients. Nevertheless, 2 patients benefitted from this treatment and had the chance to be allotransplanted.

Lenalidomide has been investigated as single agent in several trials involving pretreated PTCL patients, each enrolling a significant proportion of PTCL-NOS cases.67-70  The drug was administered orally starting dose of 25 mg/day for 21 consecutive days on a 28-day cycle. Responses rates varied between 22% and 30%, with CR rates ranging from 8% to 30%; for PTCL-NOS patients specifically, ORR varied from 20% to 43%.68-70  Response durations were short (3.6-5 months), although not substantially different than those reported for pralatrexate, romidepsin, and belinostat. AITL, rather than PTCL-NOS or other PTCL subtypes, seems to be the context in which lenalidomide reaches its best performance.69,70 

Alisertib is a selective inhibitor of Aurora A kinase, a serine-threonine kinase that localizes to centrosomes from prophase through metaphase, controls the assembly of the mitotic spindle, and regulates the mitotic process. Aurora A kinase overexpression is recognized in rapidly growing lymphoma subtypes and particularly in T-cell lymphoma.71,72  In a recently published phase 2 trial, alisertib given at the fixed oral dose of 50 mg twice daily for 7 consecutive days every 3 weeks produced an ORR of 24% in pretreated PTCL patients and 31% in the PTCL-NOS subset. Responses were seen in patients who failed prior pralatrexate or HDAC-inhibitor treatment and in nearly half of those who showed disease refractoriness.73  On the basis of these results, phase 3 randomized trials comparing alisertib with the investigator’s choice (gemcitabine, pralatrexate, romidepsin) in relapsed or refractory PTCL patients is ongoing (#NCT01482962); according to preliminary results, however, no significant efficacy benefit of alisertib vs comparators has been documented.74 

Allogeneic transplantation

Reports on alloSCT in patients with T-cell lymphomas are rare and group patients with very advanced and often refractory disease and several histology subgroups together (Table 4). Therefore, it is hard to draw unequivocal conclusions about the real clinical impact of this procedure, and no clear discriminations can be determined for different disease subtypes.75 

Table 4.

Allogeneic transplant experiences in patients with PTCL including a significant proportion of PTCL-NOS patients

ReferenceNo. of patientsConditioning, %NRM, %CR, %PFS, %OS, %PTCL-NOS
N (%)CR, %PFS, %OS, %
76 77 MA: 74 34 (5 y) 79 53 (5 y)* 57 (5 y) 27 (35) 81 58 (5 y)* 63 (5 y) 
RIC: 26 
77 52 MA: 60 27 (3 y) NA 30 (3 y) 41 (3 y) 20 (38) NR NR NR 
RIC: 40 
78 52 RIC: 100 12 (5 y) NA 40 (5 y) 50 (5 y) 23 (44) NR NR NR 
79 126 MA: 59 34 (3 y) NA 37 (3 y) 46 (3 y) 63 (50) NR 33 (3 y) 42 (3 y) 
RIC: 36 
UNKN: 5 
ReferenceNo. of patientsConditioning, %NRM, %CR, %PFS, %OS, %PTCL-NOS
N (%)CR, %PFS, %OS, %
76 77 MA: 74 34 (5 y) 79 53 (5 y)* 57 (5 y) 27 (35) 81 58 (5 y)* 63 (5 y) 
RIC: 26 
77 52 MA: 60 27 (3 y) NA 30 (3 y) 41 (3 y) 20 (38) NR NR NR 
RIC: 40 
78 52 RIC: 100 12 (5 y) NA 40 (5 y) 50 (5 y) 23 (44) NR NR NR 
79 126 MA: 59 34 (3 y) NA 37 (3 y) 46 (3 y) 63 (50) NR 33 (3 y) 42 (3 y) 
RIC: 36 
UNKN: 5 

MA, myeloablative; NR, not reported; NRM, nonrelapse mortality; RIC, reduced intensity conditioning; UNKN, unknown.

*

Indicates EFS.

The rationale behind alloSCT is that allogeneic hematopoietic stem cells are free from tumor contamination and that donor-derived immune cells are potentially capable of mediating an antitumor effect.3,76  Disease status at transplantation and chemosensitivity are outcome predictors: a significant percentage of patients in remission at the time of transplantation can be cured of their disease and OS curves reach a plateau at approximately 18 months.76-79  On the contrary, only 25% to 30% of refractory patients may take advantage of the procedure; however, the potential benefits of alloSCT in these patients can be the consequence of a potentially therapeutic graft-versus-lymphoma effect.78  No differences have been documented in relapse rates when a myeloablative regimen was compared with a reduced-intensity conditioning, although a higher rate of nonrelapse mortality with myeloablative approaches still exists.78,79 

A direct comparison of autoSCT and alloSCT in patients with PTCL in first CR, partial response, or stable disease has been provided by the Autologous or Allogeneic Transplantation in T-cell Lymphoma randomized trial80 : after 4 courses of CHOEP (given every 14 days), patients were randomized to mobilizing chemotherapy and autoSCT or to alloSCT, provided they had a 10/10 HLA-matched donor. The preplanned interim analysis on 58 evaluable patients showed no significant differences between the 2 transplant arms and no relevant improvement in terms of EFS in those allocated to the alloSCT procedure. Notably, 38% of randomized patients could not proceed to any transplantation because of early disease progression.80 

At present, alloSCT is feasible in just a few patients with relapsed PTCL because most of cases are characterized by rapid progression, clinical decay, and chemoresistance—all factors that may preclude a timely and effective application of this approach. Better OS and PFS results are obtained when alloSCT is performed early in the course of the disease and after a few treatment lines, which suggests that alloSCT should be performed as early as possible in patients with recurrent disease and preferably within a context of chemoresponsive disease.

Moving forward from CHOP: new first-line “combo” steps

Given that CHOP is regarded as the reference regimen for induction treatment of patients with PTCL, it has been used as a backbone for new first-line combination regimens that incorporate drugs demonstrating efficacy when used as single agents in relapsed or refractory patients. New first-line “combo” steps are intended to enhance CR rates, to allow a higher proportion of patients to be autotransplanted in remission, and to prolong survival. Phase 1-2 trials combining pralatrexate,81  romidepsin,82  belinostat,83  and brentuximab vedotin84  with CHOP and CHOP-like regimens have recently been published and include PTCL-NOS patients. Randomized trials comparing new drug combinations with CHOP are now ongoing (Table 5). The anti-CD52 monoclonal antibody, alemtuzumab, which worked well as a single agent in pretreated PTCL,85  has also been investigated in combination with CHOP.86-89 

Table 5.

Combination regimens including new agents for the first-line treatment of PTCL patients

CombinationPhaseStudy statusStudy descriptionAvailable resultsReference or NCT no.
Pralatrexate + CEOP Completed Alternation of CEOP and pralatrexate in untreated patients with PTCL. AutoSCT permitted in transplant-eligible patients. Pralatrexate given at 30 mg/m2 on days 15, 22, 29. Cycle duration: 6 wk. 6 planned cycles. 33 patients enrolled; 64% PTCL-NOS. 45% of patients received autoSCT. ORR, 70%; CR, 52%; 2-y PFS, 39%; 2-y OS, 60%. PFS and OS not significantly improved if compared with reported data of CHOP and CHOEP. 81 
Pralatrexate + CHOP Ongoing To find the MTD of pralatrexate in combination with CHOP in untreated PTCL. Up to 5 sequential escalating dose cohorts of pralatrexate (MAD, 30 mg/m2), given on days 1 and 8, together with CHOP. One expansion cohort with MTD of pralatrexate. Final data collection for primary outcome measures: April 2017. NCT02594267 
Romidepsin + CHOP 1/2 Completed To find the MTD of romidepsin in combination with CHOP in untreated PTCL. Three treatment cohorts of romidepsin (8, 10, 12 mg/m2) starting from 10 mg/m2. One expansion cohort with MTD of romidepsin. 37 patients enrolled. Romidepsin MTD was 12 mg/m2, given at days 1 and 8 every 3 wk. ORR, 68%; CR, 51%; 18-mo PFS, 77%. Adverse events: hematological. Cardiovascular events observed, but questionable relationship with romidepsin. 82 
Ongoing Randomized study to compare efficacy of romidepsin + CHOP vs CHOP in untreated PTCL. Romidepsin given at 12 mg/m2 on days 1 and 8 every 3 wk. 6 planned cycles. Final data collection for primary outcome measures: July 2019. NCT01796002 
Romidepsin + CHOEP 1/2 Ongoing To find the MTD of romidepsin in combination with CHOEP before autoSCT in young (<65 y) untreated patients with PTCL. Four treatment cohorts of romidepsin (8, 10, 12, 14 mg/m2) starting from 12 mg/m2. One expansion cohort with MTD of romidepsin. Final data collection for primary outcome measures: September 2017. NCT02223208 
Belinostat + CHOP Completed To find the MTD of belinostat in combination with CHOP in untreated PTCL. Five treatment cohorts of belinostat, 1000 mg/m2 for 1-5 d, together with CHOP, starting from cohort 3 (1000 mg/m2, days 1-3). One expansion cohort with MTD of belinostat. 23 patients enrolled. Belinostat MTD was 1000 mg/m2, days 1-5 (cohort 5). ORR (18 evaluable patients), 89%; CR, 72%. Adverse events: those typically seen with CHOP chemotherapy. 83 
Brentuximab + CHP Ongoing Double-blind, randomized, placebo-controlled study to compare efficacy of brentuximab vedotin + CHP (without vincristine to avoid excessive neurotoxicity) vs CHOP in CD30+ mature T-cell lymphoma (ECHELON-2 trial). Final data collection for primary outcome measures: December 2017. NCT01777152 
Alemtuzumab + CHOP Completed Alemtuzumab given at 30 mg/cycle for the first 4 (part 1) or 8 (part 2) cycles every 4 wk in combination with CHOP in untreated patients with PTCL. 24 patients enrolled; 58% PTCL-NOS. ORR, 75%; CR, 71% (50% for PTCL-NOS); 2-y FFS, 48%; 2-y OS, 53%. Relevant adverse events: infectious complications; CMV reactivation (9%). 86 
Completed Alemtuzumab given at 90 mg/cycle for 8 cycles every 2 wk in combination with CHOP in untreated patients with PTCL. 20 patients enrolled; 50% PTCL-NOS. ORR, 90% (80% for PTCL-NOS); CR, 65%; 2-y EFS, 30% (10% for PTCL-NOS); 2-y OS, 55% (30% for PTCL-NOS). 87 
Ongoing Randomized study to compare efficacy of alemtuzumab + CHOP vs CHOP, followed by autoSCT, in young (<60 y) untreated PTCL patients. Alemtuzumab given at total dose of 360 mg (then of 120 mg after amendment for toxicity). CHOP given every 14 d for 6 planned cycles (ACT-1 trial). Data presented for the first 68 patients. PTCL-NOS: 56% (A-CHOP) vs 55% (CHOP). Non–arm-specific 1-y PFS, 54%; 1-y OS, 78%. Estimated study completion date: December 2016. 88, NCT00646854 
Completed Randomized study to compare efficacy of alemtuzumab (A) + CHOP vs CHOP in elderly (>60 y) untreated PTCL patients. Alemtuzumab given at the total dose of 360 mg (then of 120 mg after amendment for toxicity). CHOP given every 14 d for 6 planned cycles (ACT-2 trial). 116 patients enrolled; 39% PTCL-NOS. CR 60% (A-CHOP) vs 43% (CHOP); 3-y PFS 26% (A-CHOP) vs 29% (CHOP); 3-y OS 38% (A-CHOP) vs 56% (CHOP). Differences in PFS and OS do not reach statistical significance. Survival not improved mostly because of treatment toxicity. 89 
CombinationPhaseStudy statusStudy descriptionAvailable resultsReference or NCT no.
Pralatrexate + CEOP Completed Alternation of CEOP and pralatrexate in untreated patients with PTCL. AutoSCT permitted in transplant-eligible patients. Pralatrexate given at 30 mg/m2 on days 15, 22, 29. Cycle duration: 6 wk. 6 planned cycles. 33 patients enrolled; 64% PTCL-NOS. 45% of patients received autoSCT. ORR, 70%; CR, 52%; 2-y PFS, 39%; 2-y OS, 60%. PFS and OS not significantly improved if compared with reported data of CHOP and CHOEP. 81 
Pralatrexate + CHOP Ongoing To find the MTD of pralatrexate in combination with CHOP in untreated PTCL. Up to 5 sequential escalating dose cohorts of pralatrexate (MAD, 30 mg/m2), given on days 1 and 8, together with CHOP. One expansion cohort with MTD of pralatrexate. Final data collection for primary outcome measures: April 2017. NCT02594267 
Romidepsin + CHOP 1/2 Completed To find the MTD of romidepsin in combination with CHOP in untreated PTCL. Three treatment cohorts of romidepsin (8, 10, 12 mg/m2) starting from 10 mg/m2. One expansion cohort with MTD of romidepsin. 37 patients enrolled. Romidepsin MTD was 12 mg/m2, given at days 1 and 8 every 3 wk. ORR, 68%; CR, 51%; 18-mo PFS, 77%. Adverse events: hematological. Cardiovascular events observed, but questionable relationship with romidepsin. 82 
Ongoing Randomized study to compare efficacy of romidepsin + CHOP vs CHOP in untreated PTCL. Romidepsin given at 12 mg/m2 on days 1 and 8 every 3 wk. 6 planned cycles. Final data collection for primary outcome measures: July 2019. NCT01796002 
Romidepsin + CHOEP 1/2 Ongoing To find the MTD of romidepsin in combination with CHOEP before autoSCT in young (<65 y) untreated patients with PTCL. Four treatment cohorts of romidepsin (8, 10, 12, 14 mg/m2) starting from 12 mg/m2. One expansion cohort with MTD of romidepsin. Final data collection for primary outcome measures: September 2017. NCT02223208 
Belinostat + CHOP Completed To find the MTD of belinostat in combination with CHOP in untreated PTCL. Five treatment cohorts of belinostat, 1000 mg/m2 for 1-5 d, together with CHOP, starting from cohort 3 (1000 mg/m2, days 1-3). One expansion cohort with MTD of belinostat. 23 patients enrolled. Belinostat MTD was 1000 mg/m2, days 1-5 (cohort 5). ORR (18 evaluable patients), 89%; CR, 72%. Adverse events: those typically seen with CHOP chemotherapy. 83 
Brentuximab + CHP Ongoing Double-blind, randomized, placebo-controlled study to compare efficacy of brentuximab vedotin + CHP (without vincristine to avoid excessive neurotoxicity) vs CHOP in CD30+ mature T-cell lymphoma (ECHELON-2 trial). Final data collection for primary outcome measures: December 2017. NCT01777152 
Alemtuzumab + CHOP Completed Alemtuzumab given at 30 mg/cycle for the first 4 (part 1) or 8 (part 2) cycles every 4 wk in combination with CHOP in untreated patients with PTCL. 24 patients enrolled; 58% PTCL-NOS. ORR, 75%; CR, 71% (50% for PTCL-NOS); 2-y FFS, 48%; 2-y OS, 53%. Relevant adverse events: infectious complications; CMV reactivation (9%). 86 
Completed Alemtuzumab given at 90 mg/cycle for 8 cycles every 2 wk in combination with CHOP in untreated patients with PTCL. 20 patients enrolled; 50% PTCL-NOS. ORR, 90% (80% for PTCL-NOS); CR, 65%; 2-y EFS, 30% (10% for PTCL-NOS); 2-y OS, 55% (30% for PTCL-NOS). 87 
Ongoing Randomized study to compare efficacy of alemtuzumab + CHOP vs CHOP, followed by autoSCT, in young (<60 y) untreated PTCL patients. Alemtuzumab given at total dose of 360 mg (then of 120 mg after amendment for toxicity). CHOP given every 14 d for 6 planned cycles (ACT-1 trial). Data presented for the first 68 patients. PTCL-NOS: 56% (A-CHOP) vs 55% (CHOP). Non–arm-specific 1-y PFS, 54%; 1-y OS, 78%. Estimated study completion date: December 2016. 88, NCT00646854 
Completed Randomized study to compare efficacy of alemtuzumab (A) + CHOP vs CHOP in elderly (>60 y) untreated PTCL patients. Alemtuzumab given at the total dose of 360 mg (then of 120 mg after amendment for toxicity). CHOP given every 14 d for 6 planned cycles (ACT-2 trial). 116 patients enrolled; 39% PTCL-NOS. CR 60% (A-CHOP) vs 43% (CHOP); 3-y PFS 26% (A-CHOP) vs 29% (CHOP); 3-y OS 38% (A-CHOP) vs 56% (CHOP). Differences in PFS and OS do not reach statistical significance. Survival not improved mostly because of treatment toxicity. 89 

Source: https://clinicaltrials.gov, accessed July 2016.

ACT, Alemtuzumab and CHOP in T-cell Lymphoma; CEOP, cyclophosphamide, etoposide, vincristine, and prednisone; CMV, cytomegalovirus; 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; MAD, maximum administered dose; MTD, maximum tolerated dose.

Conclusions

PTCL-NOS is a biologically and clinically heterogeneous disease. Anthracycline-containing regimens, mainly CHOP, followed by autoSCT in transplant-eligible patients are regarded as the standard, although the best first-line approach is yet to be defined. Several new drugs are active in relapsed and refractory patients, although these drugs do not significantly affect survival rates. Whether these drugs can be safely and efficiently combined with CHOP in newer first-line regimens is under investigation.

Authorship

Contribution: A.B. and P.L.Z. conceived the work and wrote the paper.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Pier Luigi Zinzani, Institute of Hematology “L. e A. Seràgnoli”, Via Massarenti, 9, 40138 Bologna, Italy; e-mail: pierluigi.zinzani@unibo.it.

References

1.
Pileri
SA
,
Weisenburger
DD
,
Sng
I
, et al
.
Peripheral T-cell lymphoma, not otherwise specified
. In:
Swerdlow
SH
,
Campo
E
,
Harris
NL
, et al
, eds.
World Health Organization classification of tumors of haematopoietic and lymphoid tissues
. 4th ed.
Lyon, France
:
IARC Press
;
2008
:
306
-
307
2.
Vose
J
,
Armitage
J
,
Weisenburger
D
;
International T-Cell Lymphoma Project
.
International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes
.
J Clin Oncol
.
2008
;
26
(
25
):
4124
-
4130
.
3.
Zinzani
PL
,
Broccoli
A
.
T-cell lymphoproliferative disorders
. In:
Hoffbrand
V
,
Higgs
DR
,
Keeling
DM
, et al
, eds.
Postgraduate hematology
, 7th ed.
Hoboken, NJ
:
Wiley Blackwell
;
2016
:
524
-
536
4.
Piccaluga
PP
,
Agostinelli
C
,
Califano
A
, et al
.
Gene expression analysis of peripheral T cell lymphoma, unspecified, reveals distinct profiles and new potential therapeutic targets
.
J Clin Invest
.
2007
;
117
(
3
):
823
-
834
.
5.
Iqbal
J
,
Weisenburger
DD
,
Greiner
TC
, et al
;
International Peripheral T-Cell Lymphoma Project
.
Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma
.
Blood
.
2010
;
115
(
5
):
1026
-
1036
.
6.
Piccaluga
PP
,
Fuligni
F
,
De Leo
A
, et al
.
Molecular profiling improves classification and prognostication of nodal peripheral T-cell lymphomas: results of a phase III diagnostic accuracy study
.
J Clin Oncol
.
2013
;
31
(
24
):
3019
-
3025
.
7.
Iqbal
J
,
Wright
G
,
Wang
C
, et al
;
Lymphoma Leukemia Molecular Profiling Project and the International Peripheral T-cell Lymphoma Project
.
Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma
.
Blood
.
2014
;
123
(
19
):
2915
-
2923
.
8.
de Leval
L
,
Parrens
M
,
Le Bras
F
, et al
.
Angioimmunoblastic T-cell lymphoma is the most common T-cell lymphoma in two distinct French information data sets
.
Haematologica
.
2015
;
100
(
9
):
e361
-
e364
.
9.
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
-
1469
.
10.
Sakata-Yanagimoto
M
,
Enami
T
,
Yoshida
K
, et al
.
Somatic RHOA mutation in angioimmunoblastic T cell lymphoma
.
Nat Genet
.
2014
;
46
(
2
):
171
-
175
.
11.
Cairns
RA
,
Iqbal
J
,
Lemonnier
F
, et al
.
IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma
.
Blood
.
2012
;
119
(
8
):
1901
-
1903
.
12.
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
.
13.
Boddicker
RL
,
Razidlo
GL
,
Dasari
S
, et al
.
Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma
.
Blood
.
2016
;
128
(
9
):
1234
-
1245
.
14.
Streubel
B
,
Vinatzer
U
,
Willheim
M
,
Raderer
M
,
Chott
A
.
Novel t(5;9)(q33;q22) fuses ITK to SYK in unspecified peripheral T-cell lymphoma
.
Leukemia
.
2006
;
20
(
2
):
313
-
318
.
15.
Vasmatzis
G
,
Johnson
SH
,
Knudson
RA
, et al
.
Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas
.
Blood
.
2012
;
120
(
11
):
2280
-
2289
.
16.
Wang
T
,
Feldman
AL
,
Wada
DA
, et al
.
GATA-3 expression identifies a high-risk subset of PTCL, NOS with distinct molecular and clinical features
.
Blood
.
2014
;
123
(
19
):
3007
-
3015
.
17.
Sabattini
E
,
Pizzi
M
,
Tabanelli
V
, et al
.
CD30 expression in peripheral T-cell lymphomas
.
Haematologica
.
2013
;
98
(
8
):
e81
-
e82
.
18.
Bossard
C
,
Dobay
MP
,
Parrens
M
, et al
.
Immunohistochemistry as a valuable tool to assess CD30 expression in peripheral T-cell lymphomas: high correlation with mRNA levels
.
Blood
.
2014
;
124
(
19
):
2983
-
2986
.
19.
Bisig
B
,
de Reyniès
A
,
Bonnet
C
, et al
.
CD30-positive peripheral T-cell lymphomas share molecular and phenotypic features
.
Haematologica
.
2013
;
98
(
8
):
1250
-
1258
.
20.
A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project
.
N Engl J Med
.
1993
;
329
(
14
):
987
-
994
.
21.
Gallamini
A
,
Stelitano
C
,
Calvi
R
, et al
;
Intergruppo Italiano Linfomi
.
Peripheral T-cell lymphoma unspecified (PTCL-U): a new prognostic model from a retrospective multicentric clinical study
.
Blood
.
2004
;
103
(
7
):
2474
-
2479
.
22.
Went
P
,
Agostinelli
C
,
Gallamini
A
, et al
.
Marker expression in peripheral T-cell lymphoma: a proposed clinical-pathologic prognostic score
.
J Clin Oncol
.
2006
;
24
(
16
):
2472
-
2479
.
23.
Vose
JM
.
International peripheral T-cell lymphoma (PTCL) clinical and pathologic review project: poor outcome by prognostic indices and lack of efficacy with anthracyclines [abstract]
.
Blood
.
2005
;
106
(
11
).
Abstract 811
.
24.
Weisenburger
DD
,
Savage
KJ
,
Harris
NL
, et al
;
International Peripheral T-cell Lymphoma Project
.
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
-
3408
.
25.
Ellin
F
,
Landström
J
,
Jerkeman
M
,
Relander
T
.
Real-world data on prognostic factors and treatment in peripheral T-cell lymphomas: a study from the Swedish Lymphoma Registry
.
Blood
.
2014
;
124
(
10
):
1570
-
1577
.
26.
Xu
P
,
Yu
D
,
Wang
L
,
Shen
Y
,
Shen
Z
,
Zhao
W
.
Analysis of prognostic factors and comparison of prognostic scores in peripheral T cell lymphoma, not otherwise specified: a single-institution study of 105 Chinese patients
.
Ann Hematol
.
2015
;
94
(
2
):
239
-
247
.
27.
Gutiérrez-García
G
,
García-Herrera
A
,
Cardesa
T
, et al
.
Comparison of four prognostic scores in peripheral T-cell lymphoma
.
Ann Oncol
.
2011
;
22
(
2
):
397
-
404
.
28.
Feeney
J
,
Horwitz
S
,
Gönen
M
,
Schöder
H
.
Characterization of T-cell lymphomas by FDG PET/CT
.
AJR Am J Roentgenol
.
2010
;
195
(
2
):
333
-
340
.
29.
Casulo
C
,
Schöder
H
,
Feeney
J
, et al
.
18F-fluorodeoxyglucose positron emission tomography in the staging and prognosis of T cell lymphoma
.
Leuk Lymphoma
.
2013
;
54
(
10
):
2163
-
2167
.
30.
El-Galaly
TC
,
Pedersen
MB
,
Hutchings
M
, et al
.
Utility of interim and end-of-treatment PET/CT in peripheral T-cell lymphomas: A review of 124 patients
.
Am J Hematol
.
2015
;
90
(
11
):
975
-
980
.
31.
Tomita
N
,
Hattori
Y
,
Fujisawa
S
, et al
.
Post-therapy 18F-fluorodeoxyglucose positron emission tomography for predicting outcome in patients with peripheral T cell lymphoma
.
Ann Hematol
.
2015
;
94
(
3
):
431
-
436
.
32.
Sohn
BS
,
Yoon
DH
,
Kim
KP
, et al
.
The role of 18F-fluorodeoxyglucose positron emission tomography at response assessment after autologous stem cell transplantation in T-cell non-Hodgkin’s lymphoma patients
.
Ann Hematol
.
2013
;
92
(
10
):
1369
-
1377
.
33.
Ham
JS
,
Kim
SJ
,
Choi
JY
, et al
.
The prognostic value of interim and end-of-treatment PET/CT in patients with newly diagnosed peripheral T-cell lymphoma
.
Blood Cancer J
.
2016
;
6
:
e395
.
34.
Pellegrini
C
,
Argnani
L
,
Broccoli
A
, et al
.
Prognostic value of interim positron emission tomography in patients with peripheral T-cell lymphoma
.
Oncologist
.
2014
;
19
(
7
):
746
-
750
.
35.
Savage
KJ
,
Chhanabhai
M
,
Gascoyne
RD
,
Connors
JM
.
Characterization of peripheral T-cell lymphomas in a single North American institution by the WHO classification
.
Ann Oncol
.
2004
;
15
(
10
):
1467
-
1475
.
36.
Abramson
JS
,
Feldman
T
,
Kroll-Desrosiers
AR
, et al
.
Peripheral T-cell lymphomas in a large US multicenter cohort: prognostication in the modern era including impact of frontline therapy
.
Ann Oncol
.
2014
;
25
(
11
):
2211
-
2217
.
37.
Pinter-Brown
L
,
Foss
FM
,
Carson
KR
, et al
.
Patient characteristics and initial treatment patterns in the United States for the most common subtypes of peripheral T-cell lymphoma (PTCL) [abstract]
.
Blood
.
2014
;
124
(
21
).
Abstract 4434
.
38.
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.
39.
Briski
R
,
Feldman
AL
,
Bailey
NG
, et al
.
The role of front-line anthracycline-containing chemotherapy regimens in peripheral T-cell lymphomas
.
Blood Cancer J
.
2014
;
4
:
e214
.
40.
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
-
166
.
41.
Schmitz
N
,
Trümper
L
,
Ziepert
M
, et al
.
Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group
.
Blood
.
2010
;
116
(
18
):
3418
-
3425
.
42.
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
-
379
.
43.
Arkenau
HT
,
Chong
G
,
Cunningham
D
, et al
.
Gemcitabine, cisplatin and methylprednisolone for the treatment of patients with peripheral T-cell lymphoma: the Royal Marsden Hospital experience
.
Haematologica
.
2007
;
92
(
2
):
271
-
272
.
44.
Corradini
P
,
Tarella
C
,
Zallio
F
, et al
.
Long-term follow-up of patients with peripheral T-cell lymphomas treated up-front with high-dose chemotherapy followed by autologous stem cell transplantation
.
Leukemia
.
2006
;
20
(
9
):
1533
-
1538
.
45.
Mercadal
S
,
Briones
J
,
Xicoy
B
, et al
;
Grup per l’Estudi dels Limfomes de Catalunya I Balears (GELCAB)
.
Intensive chemotherapy (high-dose CHOP/ESHAP regimen) followed by autologous stem-cell transplantation in previously untreated patients with peripheral T-cell lymphoma
.
Ann Oncol
.
2008
;
19
(
5
):
958
-
963
.
46.
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
-
113
.
47.
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
-
3099
.
48.
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
-
1976
.
49.
Dreyling
M
,
Thieblemont
C
,
Gallamini
A
, et al
.
ESMO Consensus conferences: guidelines on malignant lymphoma. part 2: marginal zone lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma
.
Ann Oncol
.
2013
;
24
(
4
):
857
-
877
.
50.
Zinzani
PL
,
Venturini
F
,
Stefoni
V
, et al
.
Gemcitabine as single agent in pretreated T-cell lymphoma patients: evaluation of the long-term outcome
.
Ann Oncol
.
2010
;
21
(
4
):
860
-
863
.
51.
Wang
ES
,
O’Connor
O
,
She
Y
,
Zelenetz
AD
,
Sirotnak
FM
,
Moore
MA
.
Activity of a novel anti-folate (PDX, 10-propargyl 10-deazaaminopterin) against human lymphoma is superior to methotrexate and correlates with tumor RFC-1 gene expression
.
Leuk Lymphoma
.
2003
;
44
(
6
):
1027
-
1035
.
52.
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
-
4364
.
53.
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
-
1189
.
54.
Santini
V
,
Gozzini
A
,
Ferrari
G
.
Histone deacetylase inhibitors: molecular and biological activity as a premise to clinical application
.
Curr Drug Metab
.
2007
;
8
(
4
):
383
-
393
.
55.
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
-
5834
.
56.
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
-
636
.
57.
Foss
F
,
Horwitz
S
,
Pro
B
, et al
.
Romidepsin for the treatment of relapsed/refractory peripheral T cell lymphoma: prolonged stable disease provides clinical benefits for patients in the pivotal trial
.
J Hematol Oncol
.
2016
;
9
:
22
.
58.
Foss
F
,
Coiffier
B
,
Horwitz
S
, et al
.
Tolerability to romidepsin in patients with relapsed/refractory T-cell lymphoma
.
Biomark Res
.
2014
;
2
:
16
.
59.
Pellegrini
C
,
Dodero
A
,
Chiappella
A
, et al
;
Italian Lymphoma Foundation (Fondazione Italiana Linfomi Onlus, FIL)
.
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
.
60.
Chihara
D
,
Oki
Y
,
Fayad
L
, et al
.
Phase I study of romidepsin in combination with ICE (ifosfamide, carboplatin and etoposide) in patients with relapsed or refractory peripheral T-cell lymphoma [abstract]
.
Blood
.
2014
;
124
(
21
).
Abstract 1748
.
61.
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
-
2196
.
62.
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
-
3100
.
63.
Lamarque
M
,
Bossard
C
,
Contejean
A
, et al
.
Brentuximab vedotin in refractory or relapsed peripheral T-cell lymphomas: the French named patient program experience in 56 patients
.
Haematologica
.
2016
;
101
(
3
):
e103
-
e106
.
64.
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
-
819
.
65.
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
-
2499
.
66.
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
-
110
.
67.
Dueck
G
,
Chua
N
,
Prasad
A
, et al
.
Interim report of a phase 2 clinical trial of lenalidomide for T-cell non-Hodgkin lymphoma
.
Cancer
.
2010
;
116
(
19
):
4541
-
4548
.
68.
Zinzani
PL
,
Pellegrini
C
,
Broccoli
A
, et al
.
Lenalidomide monotherapy for relapsed/refractory peripheral T-cell lymphoma not otherwise specified
.
Leuk Lymphoma
.
2011
;
52
(
8
):
1585
-
1588
.
69.
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
-
2876
.
70.
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
-
723
.
71.
Yakushijin
Y
,
Hamada
M
,
Yasukawa
M
.
The expression of the aurora-A gene and its significance with tumorgenesis in non-Hodgkin’s lymphoma
.
Leuk Lymphoma
.
2004
;
45
(
9
):
1741
-
1746
.
72.
Manfredi
MG
,
Ecsedy
JA
,
Chakravarty
A
, et al
.
Characterization of Alisertib (MLN8237), an investigational small-molecule inhibitor of aurora A kinase using novel in vivo pharmacodynamic assays
.
Clin Cancer Res
.
2011
;
17
(
24
):
7614
-
7624
.
73.
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
-
2404
.
74.
O’Connor
OA
,
Özcan
M
,
Jacobsen
ED
, et al
.
First multicentre, randomized phase 3 study in patients (pts) with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL): alisertib (MLN8237) versus investigator’s choice (Lumiere trial; NCT01482962) [abstract]
.
Blood
.
2015
;
126
(
23
).
Abstract 341
.
75.
Schmitz
N
,
Wu
HS
,
Glass
B
.
Allogeneic transplantation in T-cell lymphomas
.
Semin Hematol
.
2014
;
51
(
1
):
67
-
72
.
76.
Le Gouill
S
,
Milpied
N
,
Buzyn
A
, et al
;
Société Française de Greffe de Moëlle et de Thérapie Cellulaire
.
Graft-versus-lymphoma effect for aggressive T-cell lymphomas in adults: a study by the Société Francaise de Greffe de Moëlle et de Thérapie Cellulaire
.
J Clin Oncol
.
2008
;
26
(
14
):
2264
-
2271
.
77.
Jacobsen
ED
,
Kim
HT
,
Ho
VT
, et al
.
A large single-center experience with allogeneic stem-cell transplantation for peripheral T-cell non-Hodgkin lymphoma and advanced mycosis fungoides/Sezary syndrome
.
Ann Oncol
.
2011
;
22
(
7
):
1608
-
1613
.
78.
Dodero
A
,
Spina
F
,
Narni
F
, et al
.
Allogeneic transplantation following a reduced-intensity conditioning regimen in relapsed/refractory peripheral T-cell lymphomas: long-term remissions and response to donor lymphocyte infusions support the role of a graft-versus-lymphoma effect
.
Leukemia
.
2012
;
26
(
3
):
520
-
526
.
79.
Smith
SM
,
Burns
LJ
,
van Besien
K
, et al
.
Hematopoietic cell transplantation for systemic mature T-cell non-Hodgkin lymphoma
.
J Clin Oncol
.
2013
;
31
(
25
):
3100
-
3109
.
80.
Schmitz
N
,
Nickelsen
M
,
Altmann
B
, et al
.
Allogenic or autologous transplantation as first-line therapy for younger patients with peripheral T-cell lymphoma: results of the interim analysis of the AATT trial [abstract]
.
J Clin Oncol
.
2015
;
33
(suppl). Abstract 8507
.
81.
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
-
544
.
82.
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
-
e165
.
83.
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 [abstract]
.
Blood
.
2015
;
126
(
23
).
Abstract 253
.
84.
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
-
3143
.
85.
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
-
2924
.
86.
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
-
2323
.
87.
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
-
1600
.
88.
d’Amore
F
,
Leppä
S
,
Gomes da Silva
M
, et al
.
First interim efficacy and safety analysis of an international phase III randomized trial in newly diagnosed systemic peripheral T-cell lymphoma treated with chemotherapy with or without alemtuzumab and consolidated with high dose therapy [abstract]
.
Blood
.
2012
;
120
(
21
).
Abstract 57
.
89.
Trumper
LH
,
Wulf
G
,
Ziepert
M
, et al
.
Alemtuzumab added to CHOP for treatment of peripheral T-cell lymphoma (pTNHL) of the elderly: final results of 116 patients treated in the international ACT-2 phase 3 trial [abstract]
.
J Clin Oncol
.
2016
;
34
(suppl). Abstract 7500
.