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The Changing Landscape of Peripheral T-Cell Lymphoma in the Era of Novel Therapies

Seminars in Hematology, 1, 51, pages 25 - 34

Peripheral T-cell lymphomas (PTCLs) are the most common sub-entity of mature T-cell lymphomas, and apart from particular presentations, share a poor prognosis with frequent short-term, agressive, and chemorefractory relapses. Because of the rarity and also the heterogeneity of the disease, we lack randomized clinical trials. However, to date, neither intensification of frontline chemotherapy or autologous transplant has led to any improvement of survival, and the standard CHOP (cyclophosphamide, doxorubicine, vincristine, and prednisone) regimen remains the most employed as induction therapy. In the past few years, new chemotherapeutic agents, with the capability to encompass the resistance to conventional chemotherapy, such as pralatrexate or bendamustine, have been evaluated. Furthermore, identification of cell surface molecular markers (CD52, CD30, CCR4) has led to the development of new monoclonal antibodies. Similarly, the better comprehension of physiopathological mechanisms and detection of deregulated intracellular pathways encouraged the use of novel therapies such as histone deacetylase inhibitors or immunomodulatory drugs. Some of these compounds have been approved for relapse, and are currently evaluated upfront in ongoing clinical trials. Despite these efforts, the global prognosis still remains much inferior to those of B-cell lymphomas, highlighting the necessity of multicenter clinical trials.

Mature T- and natural killer (NK) cell neoplasms are a heterogeneous group of disease, resulting from clonal proliferation of mature post-thymic lymphocytes. These are rare disorders, usually affecting adults, whose incidence is much lower than that of B-cell lymphoproliferative disorders, representing fewer than 15% of all non-Hodgkin lymphomas (NHLs). 1 According to the World Health Organization (WHO) classification, there are divided into those with predominantly leukemic, nodal, extranodal, or cutaneous presentation ( Table 1 ). Excluding primary cutaneous T-cell lymphoma, which will not be described in this review, the most frequently encountered entities are part of the nodal group. This includes peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) (25.9%); angioimmunoblastic T-cell lymphoma (AITL) (18.5%); and anaplastic large cell lymphoma (ALCL) (12%), which is divided into ALK-positive (ALK-pos) and ALK-negative (ALK-neg) forms. 2 Entities from the extranodal group are much less common, and are regrouped as extranodal NK/T-cell lymphoma, nasal type (ENKTL), found preponderantly in Asian countries; enteropathy-associated T-cell lymphoma (EATL); and hepatosplenic γ/δ T-cell lymphoma. Finally, the leukemia group consists of adult T-cell leukemia-lymphoma (ATL) associated with human T-lymphotropic virus type 1 (HTLV-1), whose geographic repartition is correlated to areas where HTLV-1 is prevalent; aggressive NK cell leukemia and T-cell prolymphocytic leukemia, which are rare diseases; and T-cell chronic large granular lymphocytes leukemia (LGL), which usually follows an indolent and chronic course.

Table 1 Mature T- and NK Cell Neoplasms (WHO classification, 2008) 80

Mature T-cell leukemias
Adult T-cell leukemia/lymphoma (ATLL)
 T-cell prolymphocytic leukemia
 T-cell large granular lymphocytic leukemia
 Agressive NK cell leukemia
Nodal peripheral T-cell lymphomas (PTCLs)
Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS)
Angioimmunoblastic T-cell lymphoma (AITL)
Anaplastic large cell lymphoma (ALCL)
  ALK-positive
  ALK-negative
Extranodal PTCL
Extranodal NK/T-cell lymphoma, nasal type (ENKTL)
 Enteropathy-associated T-cell lymphoma (EATL)
 Hepatosplenic T-cell lymphom
Cutaneous T-cell lymphomas (CTCLs)
 Mycosis fungoides
 Sézary syndrome
 Primary cutaneous CD30+ T-cell lymphoproliferative disease
 Primary cutaneous PTCLs

NOTE. Underlined lymphomas are those discussed in the review.

With the exception of ALK-pos ALCL, mostly seen in infants and young adults, which has good chemosensitivity and therefore carries a good prognosis, most T-cell lymphoma patients have a grim prognosis with short progression-free survival (PFS) and overall survival (OS), as compared to patients with aggressive B-cell lymphomas. So far, in contrast to B-cell lymphomas in which the introduction of anti-CD20 monoclonal antibodies has dramatically improved survival, their prognosis has unfortunately not been significantly modified in the last decade, neither by new compounds nor by intensive procedures. Accordingly, innovative therapeutical modalities are particularly needed. However, such efforts are especially challenging because of the rarity and heterogeneity of the disease, the lack of uniformly expressed biological markers, the frequent aggressive features particularly at relapse, and, not least, the difficulty in conducting well-designed clinical trials.

This exhaustive review will first address the current options of frontline therapy, focusing on the management of PTCL-NOS but also dealing with particular procedures of less frequent subentities. Next, we will provide an overview of innovative therapeutic options, and will try to define the best strategies of use and incorporation into standard procedures in the aim to reverse the poor prognosis of the disease.

Current Options for Frontline Therapy in Peripheral T-cell Lymphomas

Due to the rarity of the disease and the lack of randomized clinical trials, there is no consensus regarding first-line therapy in PTCLs to date. Anthracycline-containing regimens are widely used, and CHOP (cyclophosphamide, doxorubicine, vincristine, and prednisone) is certainly the most employed. However, this is far from a “gold standard,” and in some studies, incorporation of anthracyclines in chemotherapy failed to clearly improve survival. 1 Thus, as compared to B-cell malignancies, despite satisfactory initial response rates, short-term relapses are frequent, occurring mainly within the first 2 years following chemotherapy, and usually predicting a particularly poor evolution of the disease. Illustrating this, a retrospective analysis of 125 nodal mature T-cell lymphomas found a complete remission (CR) rate of 51% but a 5-year OS rate of 45% in the PTCL-NOS patients. 3 Similarly, and even worse, the International Peripheral T-Cell Project, which collected more than 1,300 PTCL cases, found a 5-year OS of only 32%. 4 Since it is not metabolized by the multi-drug resistance p-glycoprotein pathway, gemcitabine has been combined with cisplatin and etoposide, but, even in the absence of randomized controlled studies, did not show any obvious superiority over CHOP. 5

The potential interest in intensified procedures, used either with more intensive induction regimen or with autografting, was addressed by several cooperative groups. Unfortunately, numerous studies failed to demonstrate any improvement with a more intensive regimen than CHOP. Among them, a large retrospective study on the experience of the M.D. Anderson Cancer Center showed similar survival between the two approaches. 6 Also, the French GOELAMS group prospectively compared the VIP/ABVD regimen (etoposide, ifosfamide, cisplatine/doxorubicin, bleomycin, vinblastine, dacarbazine) to CHOP but found no difference in terms of event-free survival (EFS) or OS. 7 Conversely, other similar institutionnal non-randomized studies found some improvements with MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone-bleomycin) or with the addition of etoposide.8 and 9 However, these series included ALK-pos ALCL patients. Finally, the GELA group conducted in a 61- to 69-year-old population a prospective randomized trial comparing standard CHOP to ACVBP (doxorubicine, cyclophosphamide, vindesine, bleomycin, prednisone) in poor-prognosis aggressive (B- and T-cell) NHL. 10 Despite a similar CR rate (58% v 56%), 5-year EFS and OS were significantly longer in the ACVBP arm (39% v 29%, P = .005 and 46% v 38%, P = .036 respectively). However, the majority (80%) of patients were treated for diffuse large B-cell lymphoma (DLBCL), and there was no subgroup analysis for PTCL patients (10%).

So far, no randomized clinical trials evaluating the role of frontline autotransplant are specifically dedicated to PTCL, 11 and only two trials, both conducted by the GELA group, incorporated T-cell lymphomas among B-cell lymphomas.12 and 13 First, the LNH87-2 trial randomized 451 high–intermediate or high-risk aggressive LNH patients in CR after four courses of an anthracycline-containing induction regimen to receive either a sequential consolidation chemotherapy or high-dose chemotherapy plus autologous stem cell transplantation (HDT-ASCT). 13 Among them, 17% had T-cell phenotype. A total of 236 patients were randomized. The 8-year OS was found to be superior in the intensive arm (64% v 49%, P = .04). However, these results should be interpreted cautiously because of the small sample size, with only 11 T-cell lymphoma patients receiving HDT-ASCT, and because non-CR patients were not autografted, which could have decreased the impact of HDT. In opposition are the results of the LNH93-3 trial, in which 370 consecutive patinets under 60 years of age with newly diagnosed aggressive NHL who had at least two adverse factors on the age-adjusted International Prognostic Index (aaIPI) were randomized to receive either four courses of ACVBP as induction therapy followed by sequential consolidation, or a shortened induction phase consisting of one cycle of CEOP (cyclophosphamide, epirubicine, vincristine, prednisone) and two cycles of ECVBP (epirubicin, cyclophosphamide, vincristine, bleomycin, prednisone) rapidly followed by a BEAM (BCNU, etoposide, aracytine, melphalan)-conditioned intensive regimen. 12 Among the evaluable patients, 55 had non-anaplastic PTCL. Results in terms of EFS and OS were in favor of the standard arm, in all subgroups, possibly because of a suboptimal induction treatment in the experimental arm. Finally, a matched-control analysis pooling the data from these two trials failed to establish a clear benefit of upfront HDT-ASCT in PTCL. 14 Other groups conducted prospective, nonrandomized trials dedicated to PTCL ( Table 2 ). The Spanish group reported, in a cohort of 74 PTCL patients receiving autotransplant in first remission, 5-year OS and PFS of 68% and 63%, respectively. 15 However, all patients were in CR before transplant, which represents a selection bias. Moreover, the inclusion of 23 patients with ALCL, whose status was not described, also may have biased these results. Indeed, the same group performed a second prospective study on 26 high-risk nodal PTCL patients, who received as induction three courses of mega-CHOP followed by BEAM-conditioning autograft. 16 Among the 19 patients who proceeded to transplant, 3-year OS and PFS were 73% and 53%, respectively, which is lower than in the previous study. Similarly, the German group conducted a prospective multicenter study on upfront autotransplant in 83 PTCL patients, excluding ALK-pos ALCL. 17 Fifty-five (66%) were transplanted, with the main reason for not proceeding to ASCT being refractory disease. Among the 56% of patients achieving post-transplant CR, 3-year OS and EFS were only 48% and 36%, respectively. Similar results were reported by Mercadal and colleagues, in 41 newly diagnosed PTCL patients (ALK-pos ALCL excluded). 18 The results were disappointing: only 17 patients proceeded to transplant, demonstrating 4-year OS and PFS of 39% and 30%, respectively. All of these data clearly illustrate the need for novel treatment strategies for PTCL.

Table 2 Prospective Studies on Frontline High-Dose Therapy and Autotransplant

Study (first author) Regimen Population Endpoints and Results Comments
Rodriguez 15 CHOP BEAM 74 PTCL (including 23 ALCL) 5-year OS/PFS 68%/63%
  • All patients in CR before transplant
  • ALK-pos ALCL included
Rodriguez 16 mega-CHOP BEAM 26 high-risk nodal PTCL 3-year OS/PFS 73%/53%
  • ALK-pos ALCL excluded
Reimer 17 CHOP 83 PTCL patients, (66% proceeded to transplant) 3-year OS/EFS 48%/36%
  • ALK-pos ALCL excluded
Mercadal 18 High-dose CHOP 41 PTCL 4-year OS/PFS 39%/30%
  • ALK-pos ALCL excluded
  • Only 17 proceeded to transplant

Finally, a large phase II study was conducted by the Nordic Lymphoma Group (NLG-T-01) in 160 patients aged 18–67 years (median, 57 years). 19 Only 115 patients underwent HDT-ASCT (72%) and 90 (47%) were in CR 3 months after the transplant. Five-year PFS and OS were 44% (95% confidence interval [CI], 36%–52%) and 51% (95% CI, 43%–59%), respectively. Patients with ALK-neg ALCL had longer survival times than those with other subtypes. These results are considered by some to demonstrate the interest and benefit of HDT-ASCT as first-line treatment if patients reached a CR, but others think that the results are only marginally better than those with chemotherapy.20 and 21 With the bias of a nonrandomized study, they may be considered as equivalent and this procedure should not be considered as standard treatment for young patients with PTCL. 22

Allogeneic Transplant

Because of the poor results using standard regimens or high-dose regimens plus autologous transplant with high relapse rates, some centers have turned to allogeneic transplant in first- line CR patients or relapsed CR patients.23 and 24 Again, survival was longer for patients transplanted in first CR than after relapse. Currently, this procedure has not proven its efficacy in PTCL over HDT-ASCT or over standard chemotherapy. A large report of the CIBMTR showed that the PFS in PTCL was less than 40% at 3 years. 25 A study is planned in Germany for young patients randomized between autolougous and allogeneic transplant as first-line treatment. 26

Treatment of Particular PTCL Subentities

ALK-Positive Anaplastic Large Cell Lymphoma

ALK-pos ALCL usually occurs at a young age (median, 30 years), most frequently in children, and accounts for approximately 3%–5% of adult NHLs, with a male predominance. 27 The majority of patients present with B symptoms and stage IV disease, with frequent extranodal involvement, although gut and central nervous system involvement occur in rare cases. 28 The favorable prognosis confered by ALK positivity is illustrated by the 5-year PFS and OS of 70% and 58%, respectively, which are comparable to DLBCL outcomes, and survival of patients with a low IPI score is even better. 28 Frontline therapy is classically based on anthracycline-containing regimens, and HDT-ASCT is usually only considered in the context of relapse.

Crizotinib, a competitive inhibitor of ALK, was developed for use in non-small cell lung carcinoma harboring ALK translocation but has shown good activity in ALK-pos ALCL. 29 In a recent report, nine children and young adults with relapsing ALCL were treated with crizotinib and eight responded.

Extranodal NK/T-Cell Lymphoma, Nasal Type

Extranodal NK/T-cell lymphoma, nasal type, is a highly aggressive disease, which is more prevalent in Asian countries (3%–10% of all NHLs) than in the Western world (<1% of all NHLs). 30 Two thirds of patients present with localized disease, classically in the nasal structures, initial disseminated disease being associated with a worse outcome. It has been suggested that tumor cells express the multidrug resistance gene, which is one of the explanations for the usually poor results obtained with CHOP or CHOP-like regimens. 31 Conversely, radiotherapy obviously plays a key role in localized disease, as illustrated by the high CR rate obtained without any additionnal systemic chemotherapy. 32 However, radiotherapy alone is clearly not sufficient to reach long-term disease control. Despite the lack of randomized trials, some phase I–II trials were conducted to evaluate the interest of incorporating into the standard regimen new chemotherapeutic agents capable of overcoming mechanisms of resistance, such as ifosfamide and cisplatine. The addition of etoposide was judged to be interesting because of the frequency of hemophagocytic syndrome. Thus, the combination of dexamethasone, etoposide, ifosfamide, and cisplatin (DeVIC regimen), associated with radiotherapy, provided better results than historical controls, with 5-year OS and PFS of 70% and 63%, respectively. 33 The incorporation of methotrexate instead of cisplatin also showed interesting results. 34 Some groups reported their experience with l-asparaginase in combination with other agents. The NK-Cell Tumor Study Group designed a new combination named the SMILE regimen, composed of steroid, methotrexate, ifosfamide, l-asparaginase, and etoposide.35, 36, and 37 Among the 38 evaluable patients with newly diagnosed extended disease or relapsed/refractory (R/R) form, 45% reached a CR for an overall response rate (ORR) of 79%, which appears to be superior to historical controls. 35 Larger studies were later conducted with the same good results. 36 Less intensive therapy was proposed by the French LYSA group, with a combination of l-asparaginase, methotrexate, and dexamethasone. 38 This was a multicenter phase II study dedicated to R/R NK/T-cell lymhoma, and the majority of patients had previously received CHOP or a CHOP-like regimen. The results were surprisingly good, with an ORR of 78%, a CR rate of 61%, and a median survival time of 12 months. Finally, a phase II study of the combination of CHOP plus l-asparaginase (six to eight cycles) followed by radiotherapy in newly diagnosed ENKTL yielded an impressive CR rate of 81%, and 2-year OS and PFS of 80%. 39 Based on these results, l-asparaginase–containing regimens are now considered to be a recommendable option in first-line treatment, with dose-adjustments for elderly or frail patients. However, no consensus exists so far regarding the potential interest of HDT-ASCT in NK/T-cell lymphoma.

Enteropathy-Associated T-Cell Lymphoma

EATL is usually seen as a complication of celliac disease but may occur in patients without a history of celiac disease. It is a tumor of intraepithelial T lymphocytes. 40 In celiac disease it occurs after a phase of indolent form called refractory celiac disease (RCD). It is not clear currently if treating the patient with early-stage RCD improves the outcome. 41 Prognosis is very poor with low responses to chemotherapy, rapid tumor growth, and survival usually of a few years. Better results have been reported with standard chemotherapy (CHOP, CHOEP, or ifosfamide, vepeside, methotrexate [IVE]/MTX) followed by high-dose therapy and autologous transplant.19 and 42 This treatment has been proposed for RCD patients with some success. 43 Alemtuzumab alone or in combination with chemotherapy has been associated with a good response in some patients. 44

New Agents in the Treatment of Relapsed/Refractory Peripheral T-Cell Lymphomas

Frequent short-term and chemorefractory relapses underly the need to develop more efficient therapies. As detailed below, current investigations schematically focus first on new chemotherapeutic agents capable of overcoming drug resistance, and second on new compounds with innovative and original mechanisms of actions, which is particularly interesting in the situations of chemorefractoriness.

Pralatrexate

Pralatrexate belongs to a new class of antifolates, structurally designed to have a higher affinity for the reduced folate carrier, leading to enhanced intracellular uptake and accumulation in the tumor cells, as compared to the more commonly used methotrexate.45 and 46 In vitro studies demonstrated a more than 10-fold greater efficacy than methotrexate in several NHL cell lines, which led to its clinical developpement. 47 On the basis of the well-known synergistic effect of methotrexate and cytarabine in a schedule-dependent manner, Toner and colleagues evaluated the combination of pralatrexate and gemcitabine in mouse models of human NHL. 48 This combination was found to be more potent that methotrexate plus cytarabine, by inducing apoptosis, caspase activation, and CR in the animal models. Also interesting was the combination of pralatrexate and the proteasome inhibitor bortezomib against several T-lymphoma cell lines. 49 First clinical experiences were obtained in lung cancers. Regarding hematologic malignancies, a first phase I trial was conducted in relapsed or refractory B- and T-cell NHL. 50 Pralatrexate was administered at a dose of 30 mg/m2 weekly for 6 weeks every 7 weeks. Supplementation with vitamin B12 and folic acid was associated with decreasing mucosal toxicity. An ORR of 54%, including CRs, was shown in T-cell lymphomas, leading to durable remissions. Based on these encouraging data, the multicenter phase II PROPEL study was initiated. 51 Study treatment was administered similarly as in the phase I trial, until disease progression. One hundred fifteen patients with relapsed or refractory T-cell lymphomas were included, comprising 59 PTCL-NOS, 17 ALCL (majority ALK-neg), and 13 AITL. It was a heavily pretreated population, with a median of three prior lines of therapy. ORR was 29%, comprising 11% CR/CRu (unconfirmed CR). Interestingly, 19% of primary refractory patients had evidence of a response to pralatrexate, suggesting its capability of overcoming the mechanisms of resistance. Responses were observed in all subgroups, although AITL showed a lower ORR. In responding patients, the median duration of response was 10.1 months. The most common adverse events were mucositis (71%), nausea (41%), and thrombocytopenia (41%). Based on these results, pralatrexate is registered in the United States for relapsing patients.

Because of its toxicity, pralatrexate is difficult to combine with chemotherapy, but a phase III study is ongoing with pralatrexate consolidation in patients responding to CHOP (NCT01420679).

Bendamustine

An open-label, phase II trial evaluated the use of bendamustine in R/R T-cell lymphomas. 52 Sixty patients, predominantly with PTCL-NOS and AITL, received bendamustine at the dose of 120 mg/m2 per day on days 1 and 2, every 3 weeks for six cycles. Fourty-five percent of patients were refractory to their last prior chemotherapy. The ORR was 50%, including CR in 28%. Most adverse events were cytopenias, mostly neutropenia. These encouraging response rates could lead to combining bendamustine with novel agents in the near future.

Histone Deacetylase Inhibitors

In recent years, histone deacetylase (HDAC) inhibitors have demonstrated antitumor activity in various types of cancers. By inducing the acetylation of both histones and other proteins, they lead to increased tumor-suppressor gene transcription, growth inhibition, cell cycle regulation, and apoptosis. 53 Among this new class of agents, romidepsin has been the most studied in PTCL. First, interesting results have been published in T-cell lymphoma cell lines. 54 Then, a phase II trial was conducted in CTCL and PTCL and showed, in the latter, an ORR of 38%, including a 18% CR rate. 55 A larger multicenter, prospective, single-arm phase II trial was conducted with the aim to confirm these results. 56 One hundred thirty-one patients with confirmed PTCL were included. Sixty-nine had PTCL-NOS, 27 had AITL, and 21 had ALK-neg ALCL. Patients had received a median of two prior systemic therapies. Thirty-eight percent were refractory to the most recent line of treatment. Romidepsin was administered at the dose of 14 mg/m2 intravenously on days 1, 8, and 15 of 28-day cycles. Treatment could be continued until progression in responders or if stable disease was present. The ORR was 25%, including 15% CR/CRu, which were equally observed in the three main subgroups of PTCL, with a median response duration of 17 months. The most common nonhematologic adverse events were nausea, infections (from all types), and fatigue, with most being of grade 1–2. Hematologic adverse events were essentially thrombocytopenia. A dose reduction was mandatory in only 11% of patients, and only 10% discontinued treatment because of drug-related adverse events. Prolongation of QT interval was rarely observed, and did not lead to significant symptoms. Romidepsin is now approved by the US Food and Drug Administration for patients with CTCL and PTCL who have received at least one line of therapy.

Based on these results, romidepsin is also now currently evaluated in combination with conventionnal chemotherapy. A phase Ib was conducted by the LYSA group with CHOP every 3 weeks and increasing dose of romidepsin at days 1 and 8. 57 A phase III comparing CHOP to romidepsin-CHOP is ongoing (NCT01796002).

Among the other HDAC inhibitors, belinostat has been tested in a large phase II study (BELIEF) in relapsed PTCL. Among the 129 patients, 26% achieved a response with 11% CR. 58 Panobinostat seems to have activity in CTCL and is currently being tested in PTCL. 59

Monoclonal Antibodies

Alemtuzumab

CD52 antigen has been shown to be expressed in approximately 40% of PTCLs, although this figure, despite some controversies, could be increased by using more sensitive methods of detection.60 and 61 Based on this experience, anti-CD52 humanized IgG1 monoclonal antibody (alemtuzumab) was introduced in clinical practice. Its efficacy as a single agent was shown in a pilot study of 14 heavily pretreated PTCL patients, with an ORR of 36%. 62 Later, a phase II trial evaluated the feasibility and the efficacy of eight courses of CHOP given with the subcutaneous administration of 30 mg of alemtuzumab at day 1 of each cycle. 44 CR was achieved in 17 (71%) of 24 patients, and the median duration of response was 11 months. However, the main concern for this drug remains its toxicity and particularly the incidence of opportunistic infections, as illustrated by the premature stop of studies combining CHOP and alemtuzumab due to excessive toxicity.44 and 63 An ongoing trial by the German High-Grade Non-Hodgkin’s Lymphoma Study Group and the Nordic Lymphoma Group randomizes patients to six courses of CHOP-14 plus alemtuzumab versus CHOP-14 alone (ACT-2 study, NCT00725231).

Brentuximab Vedotin

The use of antibody-drug conjugates (ADCs) has now entered into clinical practice for the treatment of malignant malignancies. ADCs are made up of a monoclonal antibody, conjugated to a toxin via a chemical linker. 64 After binding to its receptor, ADC-receptor complex is internalized. Once in the cytosolic compartment, cytotoxic agent is released, exerting its action and leading to cell apoptosis.

Brentuximab vedotin (BV) combines a potent antitubulin agent, monomethyl auristatin E, with a CD30-specific chimeric immunoglobulin G1 monoclonal antibody. 65 The large expression of CD30, particularly in ALCL and to a smaller degree on other subtypes of PTCL, makes it an attractive drug in T-cell lymphoma. In a phase I multicenter dose-escalation study, 45 patients, the great majority with relapsed of refractory Hodgkin lymphoma, received BV; interestingly, the two patients with ALCL both achieved CR. 66 This led to conduct a phase II trial exclusively dedicated to this subtype of PTCL. 67 Fifty-eight R/R patients (72% with ALK-neg status) were included, and received BV at the dose of 1.8 mg/kg every 3 weeks, for up to 16 doses. Sixty-two percent were considered primary refractory. An impressive objective RR of 86% was observed, including 57% CR, with a median response duration of 12.6 months. The most common adverse event was peripheral neuropathy (41% of any grade, 12% of grade 3), which resolved or improved in the majority of the patients. Cytopenias (neutropenia, thrombocytopenia) were most often manageable. These results demonstrated that BV could be suitable for patients with CD30-expressing T-cell lymphoma. Clinical trials combining BV with standard CHOP are now ongoing (ECHELON-2, NCT01777152).

Mogamulizumab

Mogamulizumab is a humanized anti-CC chemokine receptor 4 (CCR4) IgG1 monoclonal antibody with a defucosylated Fc region, thereby enhancing antibody-dependent cellular cytotoxicity. 68 Since CCR4 is expressed in most patients with ATL and based on encouraging preclinical results, early-phase trials were conducted in this subgroup of T-cell lymphoma.69 and 70 Mogamulizumab was administered as weekly infusions at the dose of 1.0 mg/kg. In the phase II part, among the 26 patients enrolled with evaluable R/R CCR4-positive ATL, an ORR of 50% was observed, including eight CRs, irrespective of the number of previous lines of therapy. Median PFS and OS were 5.2 and 13.7 months, respectively. These encouraging results led to recruitment of a larger number of patients with PTCL, in which CCR4 is sometimes also expressed, in a Japanese multicenter phase II study whose results were presented during the last International Conference of Malignant Lymphoma (ICML). 71 A total of 37 patients were enrolled (29 PTCL, 8 CTCL). The ORR was 35%, including 14% CRs. In subgroup analysis, ORRs were 34% and 38%, respectively. The most frequent adverse events observed with mogamulizumab were infusion-related reactions (89%), primarily at first infusion, rashes (63%), and grade 3–4 lymphopenia (73%), which should anti-infectious prophylactic measures be considered. Regarding skin toxicity, cases of Stevens-Johnson syndrome were reported, possibly related to the defect of regulatory T cells after treatment. 72

Others

Denileukin diftitox is a fusion protein in which the receptor binding domain of diphteria toxin has been exchanged for that of the interleukin-2 molecule. 73 A phase II study in 27 patients with R/R PTCL yielded an ORR of 48% and a CR rate of 22% but a PFS of only 6 months. 74 A phase II combining denileukin diftitox with CHOP was reported. 75

Lenalidomide, a second-generation immunomodulatory drug, was tested as a single agent (25 mg daily, on days 1 to 21 of 28-day cycles) in 23 R/R T-cell lymphoma patients. 76 Results were poor with an ORR of 30% and a median PFS of 3 months, leading to the consideration of this agent in combination. In the “Expect” study, 54 patients were treated, with an ORR of 22% and an 11% CR rate. 77

Alisertib is an inhibitor of aurora A kinase, a serine-threonine protein kinase that has a role in centromere functions and mitosis. Inhibition of aurora A kinase results in genomic instability and apoptosis. It was tested in a phase II study of aggressive lymphomas in eight patients with PTCL. 78 The ORR was 27% with four of the eight PTCL patients responding. The most common adverse events were neutropenia (63%), thrombocytopenia (33%), anemia (35%), and febrile neutropenia (13%). Based on these results, a phase III study comparing alisertib to gemcitabine, pralatrexate, or romidepsin is ongoing (NCT01482962).

Finally, scarce data on plitidepsin, in which PTCLs are only part of small subgroups, are provided by early-phase trials, which do not allow any clear conclusions to be drawn. 21

Improving Frontline Therapy of Peripheral T-Cell Lymphomas: Future Directions

With the exception of ALK-pos ALCL, the poor results obtained either with CHOP or CHOP-like regimens or with intensified therapy underlie the need for new regimens and currently lead to the addition of novel agents to our standard procedures. In a phase Ib/II study, the French LYSA group aimed to evaluate the addition of romidepsin to standard CHOP (Ro-CHOP) in first-line treatment of previously untreated PTCL. 57 The starting dose of romidepsin was 10 mg/m2 on days 1 and 8. Patients were planned to receive eight cycles. Eigtheen patients were evaluable for toxicity during the first two cycles. The main toxicities were hematologic, primarily thrombopenia around days 8–10 and sometimes requiring transfusional support, and digestive problems with nausea and vomiting most often of grade 1–2. No significant cardiovascular events obviously related to study treatment were reported. Based on this experience, the recommended dose of romidepsin for the phase II was 12 mg/m2 on days 1 and 8. With a still short median follow-up, the reported ORR is 78% with a CR rate of 66%. Phase II has now been completed and the phase III trial, randomizing newly diagnosed PTCL patients to Ro-CHOP versus standard-of-care CHOP is now recruiting (NCT01796002).

Also conducted by the French cooperative group, a currently recruiting phase II study aims to evaluate the combination of CHOP and lenalidomide in previously untreated AITL. This subset of PTCL, which is more frequent in Europe than in North America and Asia, has a particularly poor prognosis with a 5-year OS of approximately 30%, which has not been significantly influenced by intensive procedures. 79 Specific to the disease is its frequent association with autoimmune phenomena (hemolytic anemia, peripheral thrombopenia, rheumatoid arthritis–resembling manifestations), and with polyclonal hypergammaglobulinemia, reflecting expansion of the B-cell compartment. The immunomodulatory effects of lenalidomide, such as cytokine modulation (and the capacity to alter the tumor cell microenvironnement, which is thought to play a major role in AITL), enhancement of natural NK and T-cell antitumor activity, and also its antiangiogenic properties have led investigators to consider its use in frontline therapy, in combination with CHOP (NCT01553786).

Regarding antibody-drug conjugates, a randomized, double-blind, placebo-controlled phase III study of BV and CHP (=CHOP without vincristine) versus CHOP in the frontline treatment of patients with CD30 mature T-cell lymphomas in now open to enrollment (ECHELON-2, NCT01777152).

Conclusion

To date, most subtypes of PTCL, which often share aggressivity and chemorefractoriness, still carry a poor prognosis and the median survival appears to be particularly short at the time of relapse. Until now, no intensified procedure has shown any superiority over standard CHOP, which is currently the most employed upfront regimen. New compounds have recently emerged, which have been approved as single agents in relapse or refractory forms, and which are now combined in frontline regimens in the context of ongoing clinical trials. In the last few years, much effort has been made to identify new molecular targets, such as CD52, CD30, and more recently CCR4, and also to deregulated molecules within oncogenic pathways, leading to the development of new targeted therapies. Inclusion of patients in multicenter clinical trials appears to be an essential goal in order to improve the treatment of these complex and severe hematologic malignancies.

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Footnotes

Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Hematology Department, Pierre-Benite, France

lowast Address correspondence to Bertrand Coiffier, MD, Hematology Department, Centre Hospitalier Lyon Sud, 165, Chemin du Grand Revoyet, 69495 Pierre-Benite, France

Conflicts of interest: B.C. has been part of advosiry boards for Celgene, Millennium, and Spectrum.