Peripheral T-cell lymphoma, not otherwise specified

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 

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 subgroups^4-7 : 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.

Several prognostic scores have been proposed to provide a clinical stratification of PTCL-NOS patients^20-23  (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 

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 groups^20-27  (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.

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 treatment^30,31  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 OS^29,33  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 

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.

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).

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 

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).

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 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 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 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.

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 

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 

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.

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 

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.

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.