Review

Emerging drugs for T-cell lymphoma

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Michael Dickinson† & Henry Miles Prince Peter MacCallum Cancer Centre and University of Melbourne, Division of Cancer Medicine, Victoria, Australia

1.

Background

2.

Medical need

3.

Existing treatment

4.

Current research goals

5.

Scientific rationale and competitive environment

6.

Potential development issues

7.

Conclusion

8.

Expert opinion

Introduction: T-cell lymphomas are rare and conventional treatments are not typically curative. Integration of biologic agents into routine practice is especially difficult given the breadth of emerging drugs currently or recently in trials. Areas covered: This is an overview of the management of T-cell lymphoma as it stands today. The authors review clinically active biological and novel chemotherapeutic agents, which have a niche in current practice or are being actively developed and have a potential future role in the management of this challenging group of diseases. Clinical trial data were retrieved from journals and current major conference proceedings following interrogation of online search engines Expert opinion: Pralatrexate, the histone deacetylase inhibitors and brentuximab vedotin have reached the market and have provided new and useful treatment options. No novel agent has yet demonstrated a survival advantage for patients with this disease, or shown an ability to improve the low response rate to first-line chemotherapy that these diseases frequently exhibit. New randomized studies of these emerging drugs that may finally move the field forward with evidence of superiority from large Phase II and III trials currently open to accrual. Keywords: histone deacetylase inhibitors, new agents, pralatrexate, T-cell lymphoma, treatment Expert Opin. Emerging Drugs (2014) 19(2):201-213

1.

Background

Peripheral T-cell lymphomas (PTCLs) are a rare, clinically and biologically heterogenous group of lymphomas, which account for ~ 12% of cases of non-Hodgkin lymphoma (NHL), occurring at a rate of ~ 1.1 -- 1.8 per 100,000 per year [1-3]. As a result, less is known about their biology compared with more common malignancies and the market for new agents is smaller. Nonetheless, we have seen significant advances in therapy with a number of novel compounds proving efficacious. To date, most new agents for T-cell lymphoma have been used as salvage therapy and generally given as monotherapy; however, combinations are being actively explored in trials. In this review, we will limit our discussion to treatment of the mature, non-cutaneous PTCL as the primary cutaneous lymphomas have a different spectrum of treatment options and different treatment paradigm from the nodal T-cell lymphomas [4]. Rather than reviewing all agents which have been tested against T-cell lymphoma we focus on novel therapies that have either achieved recent marketing approval, are close to market, or that have retained a therapeutic niche despite limited market potential. Disease subtype considerations The WHO 2008 classification of lymphoma lists 14 subtypes of noncutaneous PTCL (Table 1) which may be distinguished from each other by particular clinical, 1.1

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Table 1. WHO classification of T-cell lymphoma 2008 and CD30 status. Key epidemiology T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Chronic NK lymphoproliferative disorders Aggressive NK cell leukemia

More prevalent among Asian populations EBV association

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EBV-positive T-cell lymphomas of childhood Adult T-cell leukemia/lymphoma

HTLV-1 associated lymphoma (occurs in 2.5% of HTLV-1 -infected) More common in Asian populations

Extranodal NK/T-cell lymphoma, nasal type Enteropathy-associated T-cell lymphoma Hepatosplenic T-cell lymphoma Angioimmunoblastic T-cell lymphoma Anaplastic large-cell lymphoma, ALK positive

Rare < 1% NHL

Anaplastic large-cell lymphoma, ALK negative Mycosis fungoides

Primary cutaneous CD30-positive T-cell LPD (including cutaneous-anaplastic large-cell lymphoma, lymphomatoid papulosis) Subcutaneous panniculitis-like T-cell lymphoma Other rare primary cutaneous lymphoma subtypes PTCL NOS

Most common PTCL subtype

CD30 status Negative Negative Negative Variable

Negative Large transformed cells may be CD30+ Occasional cases positive Usually CD30+ Negative Variable Strongly positive, especially in larger cells Homogenous strong expression Variable, more common in aggressive transformation or pagetoid reticulosis subtype Invariably positive

Negative Rare Variable

ALK: Anaplastic lymphoma kinase; EBV: Epstein--Barr virus; HTLV-1: Human T-lymphotrophic virus type 1; NHL: Non-Hodgkin lymphoma; NK: Natural killer; NOS: Not otherwise specified; PTCL: Peripheral T-cell lymphoma.

histological and immunohistochemical features. All subtypes can be thought of as rare. Although there is considerable geographic variation of the incidence of PTCL, generally a third of cases are classified as PTCL not otherwise specified (NOS). PTCL (NOS) represents a histologically heterogenous group of tumors that evade specific classification. Angioimmunoblastic T-cell lymphoma (AILT) accounts for approximately a fifth of PTCL and anaplastic large-cell lymphoma (ALCL) ~ 10% [5]. The remaining subtypes are therefore very scarce. 1.1.1

Specific entities with targeted therapy Anaplastic large-cell lymphoma

1.1.1.1

ALCL has specific druggable targets not shared by other PTCL subtypes. First, it has strong and uniform expression of the CD30 antigen. CD30, previously called Ki-1, is a member of the tumor necrosis factor receptor superfamily [6] first found to be expressed on Hodgkin lymphoma (HL) cell lines [7]. ALCL may be further divided into primary cutaneous ALCL (confined to the skin at initial presentation) and primary systemic ALCL. Loss of T antigens occurs in a minority of cases and gives a ‘null’ phenotype [8], and a breast implant-associated form has recently been described [9]. Systemic ALCL may exhibit overexpression of the anaplastic lymphoma kinase (ALK) protein, which arises from novel translocations involving the ALK and typically the nucleophosmin 202

gene. This represents a second druggable target for this disease as we shall discuss below. While relatively rare when presenting in older patients, ALK overexpression may occur in 80% of cases presenting in the first to fourth decades of life [10]. Expression of ALK is absent in the primary cutaneous ALCL and in the ALK-negative subtype of systemic ALCL, more common in older patients. The cutaneous and ALK-positive systemic forms have a better prognosis than ALK-negative ALCL and other forms of PTCL [10]. 1.1.1.2 Human T-lymphotrophic virus type 1 associated T-cell disease

Adult T-cell leukemia/lymphoma (ATL) is associated with infection by the human T-lymphotrophic virus type 1 (HTLV-1) and shares its geographical preponderance in Japan, the Caribbean as well as other sites of endemic infection in the south east of the USA, Peru and Iran [8]. Four clinical variants have been described [8,11]. 1.1.1.3 Extranodal natural killer/T-cell lymphoma, nasal type

Extranodal natural killer (NK)/T-cell lymphoma, nasal type, is most common in Asia and Central and South America and in these regions may account for 5 -- 10% of cases of NHL [8,12]. The tumor cells are positive for Epstein--Barr virus (EBV) and express cytotoxic and NK cell surface markers.

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Emerging drugs for T-cell lymphoma

Typically, this disease presents with nasal or palatal symptoms and an associated locally invasive mass with a propensity for direct extension into surrounding tissues over time. 2.

Medical need

New treatments are needed both for newly diagnosed patients and those in relapse, as is discussed below.

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3.

Existing treatment

PTCL typically presents with systemically advanced disease. Remission induction is usually attempted with conventional combination chemotherapeutic regimens such as CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone for 6 -- 8, 21-day cycles), which is considered by many to be the standard of care. Rates of complete remission (~ 50%), 5-year progression-free survival (PFS, ~ 40%) and overall survival (30 -- 40% for PTCL NOS/AILT) are considered by most to be unsatisfactory [13-15]. Indeed, compared with B-cell NHL, ability to achieve that critical first remission in PTCL remains a challenge with conventional doses of chemotherapy. One can be less pessimistic about the outcomes of systemic ALK+ ALCL following CHOP. A post-hoc analysis of several prospective studies in Germany [15] confirmed earlier observations [5,10,14,16] that ALK+ ALCL has a 5-year overall survival of 80% following treatment with CHOPlike chemotherapy. Furthermore, the addition of etoposide appears to provide further benefit albeit with additional toxicity [15]. With the exception of this subtype, conventional-dose combination chemotherapy provides inadequate long-term outcomes. As a consequence and despite the lack of randomized studies, autologous stem cell transplantation (ASCT) has been widely accepted as a consolidation treatment for patients (other than those with ALK+ ALCL) in first remission on the basis of retrospective studies suggesting an improved longterm outcome [17]. This intensive treatment is not feasible for many older or frailer patients, and the 5-year PFS was, nevertheless, only 44% in a study of 115 patients in a Phase II study [18,19]. Allogeneic transplantation may be considered in individual cases, with results thought to be comparable to patients with relapsed aggressive B-cell lymphoma, with overall survival of ~ 50% at 5 years in selected groups [20]. Intensification of chemotherapy beyond CHOP in induction has not been shown to improve survival outcomes in larger case series [21]. Consequently, regimens containing other conventional chemotherapies are under active investigation. A large prospective randomized multi-centre study in the UK is currently assessing whether the gemcitabine-/cisplastinbased protocol GEM-P will improve upon CHOP in the firstline setting based on hopeful results from the Royal Marsden

Hospital demonstrating a response rate of 73% in 23 treated patients [22,23]. With respect to NK/T-cell lymphoma, radiotherapy is prioritized above systemic therapy and may lead to long remissions in over half of patients as a monotherapy [24]. Outcomes may be better with concurrent chemoradiotherapy with cisplatin [25] or combination-carboplatin-based chemotherapy [26]. Consolidation chemotherapy is recommended in early stage disease to prevent local and systemic relapse. Combination chemotherapy incorporating asparaginase has been adapted as treatment for advanced stage disease. L-Asparaginase is highly active in NK/T-cell lymphoma, and the recently published SMILE regimen incorporating this together with high-dose methotrexate, etoposide, ifosfamide and steroid has been adapted as a standard of care in advanced and relapsed disease [27]. ATL is also managed differently from other PTCL. Overall survival following CHOP chemotherapy appears to be inferior to the more complex-to-deliver VCAP-AMP-VECP, especially in younger patients with adequate performance status [28]. Antiretroviral therapy with zidovudine and interferon-a has some evidence supporting it in those with the acute, chronic and smoldering variants of the disease but it appears less useful in lymphoma-type ATL [29]. The chronic and smoldering forms of the disease may be observed initially or treated with zidovudine [30]; however, the more progressive forms of the disease and the lymphoma variant in particular is treated with combination chemotherapy initially [30]. As will be discussed below, a novel chemokine receptor 4 (CCR4) antagonist has demonstrated activity in this disease. Patients with PTCL who have resistant/relapsed disease after first-line therapy have a dismal survival outcome when treated with conventional chemotherapy. Median PFS has been estimated at 3 months and overall survival of 5.5 months [31]. In this setting, gemcitabine alone (at a dose of 1200 mg/m2 weekly for 3 weeks of a 4-week cycle) or in combination with platinum, alkylator or vinca alkaloid is a common treatment choice [32,33]. The overall response to monotherapy may be as high as 55%, with durable responses seen in a significant subset of patients, but few cures. 4.

Current research goals

Current research is focused on finding new agents, exploring combinations and integrating the new agents into first-line care as is discussed below.

Scientific rationale and competitive environment

5.

For an overview, readers are referred to Table 2. Histone deacetylase inhibitors The histone deacetylase inhibitors (HDACi) represent one of the first drug classes to have a putative epigenetic mechanism 5.1

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Table 2. Competitive environment: novel agents for peripheral T-cell lymphoma. Compound

Romidepsin

Class/mechanism of action Histone deacetylase inhibitor

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Belinostat Panobinostat

Company

Approved disease indications

Celgene

Relapsed CTCL Relapsed PTCL

TopoTarget/Spectrum Novartis

None Pursuing myeloma indication Relapsed PTCL

Pralatrexate

Anti-metabolite

Mundipharma

Brentuximab vedotin

Antibody-toxin conjugate

Seattle genetics, Millenium/Takeda

Crizotinib

ALK inhibitor

Pfizer

Alemtuzumab

Anti-CD52 antibody

Genzyme

Mogamulizumab

Anti-CCR4 antibody

Bendamustine

Purine analogue/alkylating agent

Kyowa Hakko Kirin/ Amgen Mundipharma/Janssen

Alisertib

Aurora kinase inhibitor

Relapsed CD30+ T-cell lymphoma and Hodgkin lymphoma Non small cell lung cancer (ALK+) Relapsed CLL

Millenium/Takeda

CCR4+ ATL B-cell lymphoma CLL None

Stage of development for PTCL Randomized Phase II relapsed disease completed Randomized Phase III -- up-front treatment underway Phase II relapsed setting No development underway for PTCL Pivotal Phase II in relapsed setting complete Randomized Phase III front-line Pivotal Phase II relapsed setting complete Phase Ib for ALK+ ALCL in relapse [94] Multiple Phase II. No further development planned Single-arm Phase II studies Single Phase II study; combination studies with brentuximab underway Randomized Phase III in relapsed setting underway

ALCL: Anaplastic large-cell lymphoma; ALK: Anaplastic lymphoma kinase; ATL: Adult T-cell leukemia/lymphoma; CD: Cluster of differentiation; CCR4: Chemokine receptor 4; CLL: Chronic lymphocytic lymphoma; CTCL: Cutaneous T-cell lymphoma; PTCL: Peripheral T-cell lymphoma.

of action. The term epigenetics refers to those cellular mechanisms that alter gene expression without altering the genetic code itself. The primary mechanism of action is thought to be inhibition of specific HDACs, a group of enzymes that are responsible for deacetylating lysine residues on histone tails. Histone acetylation status is positively regulated by histone acetyl transferases. Acetylation of lysine tails leads to relatively open chromatin conformation and de-repression of gene expression. HDACs also target nonhistone proteins such as the STAT proteins, HSP90, NF-KB and p53 [34]. The overall therapeutic effect of HDACi is the selective induction of apoptosis in malignant cells. In addition, HDACi induce cell cycle arrest, cellular senescence, autophagy and immune modulation, effects which impact on rational choice of combination partner [34]. A number of immune effects have been observed; however, whether these are driver effects with respect to clinical disease response is unknown. Despite a large literature demonstrating effects of the HDACi on multiple signaling pathways, it is unknown which is most important for the therapeutic effect of this class of drugs [34,35]. HDACi were first shown to be effective in cutaneous T-cell lymphoma (CTCL), and here, the prototype is vorinostat. 204

Vorinostat is an orally available hydroxamic acid-derivative, pan-HDACi, so called because it inhibits both class 1 and class 2 HDACs, which contrasts with the relatively specific HDAC target of the other approved agent, romidepsin. Vorinostat is marketed for use in CTCL in patients refractory to two lines of conventional therapies. Vorinostat is not marketed for PTCL [36] but has been combined with chemotherapy for PTCL (NCT00601718, results awaited). Romidepsin The development of romidepsin, a cyclic peptide, closely followed that of vorinostat. Chemically unrelated to vorinostat, romidepsin is delivered intravenously over 4 h weekly for 3 weeks out of four. It relatively specifically targets class 1 HDACs. Its label indication in the USA is for the treatment of CTCL or PTCL for patients failing first-line systemic therapy or CTCL with one prior systemic therapy. Both vorinostat and romidepsin induce complete or partial remissions in ~ 20 -- 35% of patients with CTCL and are also effective in reducing disease-associated symptoms [37]. Romidepsin has been assessed as monotherapy for PTCL in two large pivotal trials; responses are summarized in Table 3. 5.1.1

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Emerging drugs for T-cell lymphoma

Table 3. Responses to romidepsin for peripheral T-cell lymphomas.

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ORR (CR + PR), n (%) CR, n (%) PR, n (%) SD, n (%) PD/NE, n (%)

Coiffier et al. [38], n = 130

Piekarz et al. [95], n = 45

38 (29)

17 (38)

19 17 22 70

8 (18) 9 (20) 5 (11) 23 (51)

(15) (13) (17) (54)

In the setting of relapsed disease, CR: Complete response; NE: Not evaluable; PD: Progressive disease; PR: Partial response; SD: Stable disease.

The 130-patient pivotal study [38] included PTCL NOS (53%), AILT (21%) and ALK-1-negative ALCL (16%) together with the other rarer diseases. Patients had received a median of two prior therapies. The overall response rate was 24%. Although only a minority of patients respond to this expensive drug, those who do may enjoy a prolonged response. In this trial, the median duration of response was 17 months with one patient maintaining a response beyond 3 years. These prolonged responses come at the practical and financial cost of on-going maintenance treatment, which, as this in an intravenous drug, comes at some considerable inconvenience to the patient. Nevertheless, this degree of activity is clinically important for disease refractory to conventional therapies where patients have no other treatment options. Most patients who do respond will do so within 8 weeks of treatment, so a 2-month trial to determine if a patient has stabilization or improvement could be considered an adequate test of the drug in an individual case. Indeed, a considerable proportion of patients have disease stabilization that generally warrants ongoing treatment to control symptoms. The key side effects of romidepsin are fatigue, altered taste, gastrointestinal upset and dose-dependent thrombocytopenia. Romidepsin and the other HDACi have been associated with the prolongation of corrected QT interval (QTc). Although not shown to be clinically significant, care not to combine this agent with other drugs known to prolong the QTc is strongly advised. Efforts are being made to move romidepsin to front-line treatment for PTCL. The French Lysa group has commenced a multinational randomized study of CHOP with or without romidepsin for front-line treatment of PTCL. Romidepsin is delivered at a dose of 12 mg/m2 on Days 1 and 8 of each 21-day CHOP cycle. In the Phase I study, the combination led to a more severe cytopenias than expected by CHOP alone. The randomized study is ambitious. If successful, it will recruit 420 patients over 43 months, the largest ever prospective study in this disease. Romidepsin is approved for PTCL after failure of at least one systemic therapy in the USA. The European Union (EU) rejected Celgene’s application for approval of

romidepsin for PTCL in July 2012, and confirmed this decision following a request from the company for re-examination in November of the same year. The drug is registered in Australia but is not currently reimbursed. There is little doubt that romidepsin will continue to be a valuable drug for PTCL; however, combination partners are being actively tested in an attempt improve on modest response rates. Belinostat Belinostat is a hydroxamic-acid derivative HDACi. Five of 20 patients in a Phase II study of belinostat 1 g/m2 i.v. over 30 min daily for 5 days of a 21-day cycle responded, with a median duration of response of ~ 5.5 months [39]. Results of the BELIEF study were reported at the ASCO meeting, 2013 [40]. In the study, 129 patients were treated, and a response rate of 26% (10% CR [complete response], 16% PR [partial response]) was reported. As observed with romidepsin, responses occurred following two cycles of treatment (median 5.6 weeks for belinostat). Duration of response was a median of 8.3 months, the longest observed was 29.4 months. Belinostat caused myelosuppression numerically less frequently than observed in the romidepsin trials (thrombocytopenia in 13%, neutropenia 13%, anemia 10%), and importantly, dose reductions and delays were not common in patients with platelets < 100  109/l. The detail of these results is awaited. It appears that the overall response rate and response kinetics associated with belinostat treatment are comparable to romidepsin and that a case is being built for combination studies going forward. 5.1.2

Panobinostat Panobinostat is an orally available hydroxamic derivative that has been the subject of large Phase II trials in both CTCL and HL. Unfortunately, response rates and durations were insufficient to allow registration for these indications and development of this agent for these indications has been halted. The detail of these studies has been discussed in prior reviews [41,42]. Results of randomized studies in myeloma have, according to a Novartis press release, been positive. Results are expected at ASCO 2014. 5.1.3

Pralatrexate Pralatrexate is a dihydrofolate reductase inhibitor that has a higher affinity for the reduced folate carrier type-1 than methotrexate, giving it higher intracellular concentration, higher potency and activity over methotrexate in animal models [43-46]. The initial observation suggesting pralatrexate may be useful for PTCL that came when remission was achieved by all four patients with PTCL in a Phase I study in which none of the B-cell lymphomas objectively responded [45]. Ten of 20 patients with PTCL in a subsequent expansion study responded to treatment [47]. A pivotal study of 111 patients (‘PROPEL’) demonstrated a response rate of 27% in 109 evaluable patients including a CR rate of 11% 2 [48]. The treatment consisted of pralatrexate 30 mg/m weekly 5.2

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for 6 weeks of a 7-week cycle and was continued until disease progression, unacceptable toxicity or physician choice. Of responders, approximately two-thirds did so after the first cycle of treatment. Duration of response was 10 months but similar to romidepsin, PFS of the overall group was only 3.5 months. All PTCL types were included, and there was no apparent difference between disease response subtypes. Prior anthracycline or platinum exposure does not appear to reduce the likelihood of response [49,50]. The key toxicity, stomatitis is less frequent if patients receive injections of vitamin B12 every 8 -- 10 weeks and receive oral folic acid 1.0 mg daily [51] and this should be considered as standard supportive care. Despite these precautions, mucositis occurred in 70% in PROPEL; 22% grade III/IV [47,52]. Thrombocytopenia (33% grade III/IV in PROPEL) may also be dose-limiting. Lower doses are being pursued for patients with CTCL [53]. Pralatrexate has been approved as monotherapy for relapsed T-cell lymphoma by the FDA in the USA [52,54]. It has orphan drug approval in the EU, Korea and Australia. Pralatrexate is currently being assessed in large randomized studies as a maintenance treatment following CHOP chemotherapy in the first-line setting. The key limitation with the drug is the requirement for protracted treatment so if positive following the randomized trial, efforts will need to be made to identify the subset of patients most likely to benefit from the treatment. Brentuximab vedotin Brentuximab vedotin (SGN35) is an antibody to CD30 conjugated to monomethyl auristatin-E, a microtubule toxin [55,56]. Upon binding, the antibody-immunotoxin conjugate is internalized. The cell dies due to direct effect of the toxin on the spindle apparatus of the cell, and it is thought that surrounding cells are also affected by the toxin regardless of their CD30 expression through leakage of the toxin into the surrounding microenvironment. Previous monoclonal antibodies SGN30 and iratumumab had limited activity in ALCL, which appears to have been far surpassed by this newer agent [55]. Brentuximab vedotin is highly active in ALCL, a CD30+ disease. It is an intravenous agent, delivered at a dose of 1.8 mg/kg over 30 min every 3 weeks until disease progression, unacceptable toxicity, or 16 cycles are delivered [57]. In a pivotal Phase II study that led to rapid approval of the drug by the FDA [58], 50 of 58 patients (86%) with relapsed ALCL achieved an objective response, with complete remission in 33 patients (57%). Patients had received a median of two prior therapies. One-fifth of patients had no response to any prior therapy and half were refractory to their immediate prior therapy. Seventy-two percent of patients were ALK negative. All but one patient had a measurable reduction in tumor bulk. PFS was 13.3 months, and 70% of patients were alive at 12 months. Grade III/IV neutropenia occurred in 21%; grade III/IV thrombocytopenia occurred in 14%. Importantly, the grade III/IV neuropathy that occurred in 5.3

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12% appears to be reversible in many cases upon dose interruption or reduction. In all, this is a well-tolerated agent and the hematological toxicity may well reflect the degree of prior exposure. This is a strikingly effective monotherapy for ALCL, and it was similarly active in the more common CD30+ HL [59]. There is a consensus that this drug will change the management of these diseases in the setting of relapse and is especially promising in the first-line setting where data is awaited. However, those patients who achieve less than a complete response to therapy generally do poorly, with those achieving a PR having a median PFS of only 4.2 months and those with stable disease progressing at only 2.7 months. It is unknown what degree of CD30 positivity is required for brentuximab vedotin’s activity. The experience in cutaneous lymphomas suggests that the drug may be active against lymphoma with low CD30 expression (< 10%) [60]. A wider experience of brentuximab in other CD30+ PTCL entities, including those with variable CD30 expression, is needed. Combinations with chemotherapy have already been tested and are safe, and larger randomized studies to test efficacy in the front-line setting in combination with cyclophosphamide, prednisolone and doxorubicin (CHP) are underway [61]. Hopefully, effective combinations will one day reduce the need for prolonged maintenance. Brentuximab vedotin is registered for use as monotherapy for relapsed ALCL and HL globally and has orphan drug status for the treatment of mycosis fungoides (a form of CTCL) in the USA [57]. Targeting ALK ALK overexpression is an attractive biological target in patients with ALCL harboring ALK translocations. Such translocations are also seen in other malignancies, most importantly a subset of non-small cell lung cancers, which express the EML4-ALK fusion oncogene, and a subset of neuroblatomas [62]. The presence of ALK fusion proteins across a number of malignancies has led to the development of a number of small molecule inhibitors of ALK, of which crizotinib is the prototype [62]. Case reports have been published of striking complete remissions to this ALK inhibitor in patients with highly chemorefractory PTCL. In some cases, it has been used as a bridge to allotransplantation [63-66]. At the American Society of Hematology (ASH) Meeting in 2013, 15 cases were presented and the overall response and complete remission rates were 60 and 30%, respectively [67]. Strikingly, given the aggressive nature of these lymphomas, the median duration of treatment was 33 weeks (range 0.1 -- 117), implying that responding patients enjoyed a protracted benefit. Of 11 patients, 10 responded in recent case series, with four patients maintaining their complete response beyond 21 months, one to > 40 months of observation [66]. ALK-positive lymphomas are being treated in early phase studies of a number of other ALK/MET inhibitors. Results of these trials are eagerly awaited; no ALK inhibitor is 5.4

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currently registered for ALK+ lymphoma, however, there is considerable potential for these agents for the treatment of this rare group of patients. At least in the case of crizotinib, it is likely that orphan indication status will be sought based on these striking case series.

maintenance in patients with minimal disease or after autologous transplantation. It has global licensing for myeloma and myelodysplasia with deletion of 5q but is not labeled in any jurisdiction for PTCL as monotherapy. Alemtuzumab Alemtuzumab (Campath-1H) is an anti-CD52 monoclonal antibody that has been tested alone or in combination with chemotherapy for T-cell lymphoma. CD52 is considered as a pan-lymphoid marker but is expressed variably in PTCL [79]. It is registered for relapsed or refractory chronic lymphocytic leukemia (a B-cell neoplasm, CLL) and is routinely used in some centers as a T-cell-depleting agent for prophylaxis against graft versus host disease in allotransplantation. Importantly, alemtuzumab has recently been withdrawn from the market across the world in preparation for its re-launch as a medication for autoimmune disease (particularly multiple sclerosis) but may be obtainable through compassionate access programs. Although deliverable subcutaneously, alemtuzumab is preferred as an intravenous agent for T-cell prolymphocytic leukemia (TPLL) where superiority of this route has been demonstrated [80]. The dose is typically 30 mg three times a week for up to 12 weeks. Its key toxicity is opportunistic infection resulting from T- and B-cell depletion. Particularly important is cytomegalovirus (CMV) re-activation [80]. As a monotherapy, alemtuzumab has modest activity in PTCL with 5 of 14 patients responding in one trial [81] and 6 of 10 responding in another, where patients were treated with a lower dose of 10 mg three times a week [82]. Six patients in the former trial and one in the latter experienced reactivation of CMV. This low-dose regimen is now generally preferred in the setting of CTCL because of the perceived improved toxicity profile. The combination of the standard-dose alemtuzumab with CHOP-14 chemotherapy appears to have unacceptable toxicity in terms of opportunistic infection. Despite a response rate of 90% in a trial of 20 patients where this combination was tested [83] and where intensive prophylaxis against infection was used, the authors concluded that the PFS was poor at 10 months and did not justify the risk of infection. Indeed, three patients developed secondary EBV-associated lymphoma following treatment. Similar infections rates had occurred in another study this time testing alemtuzumab at a dose of 90 mg, which was terminated following recruitment of 20 patients [84]. Despite these findings, two prospective randomized studies of CHOP-14 with or without alemtuzumab 30 mg given for the first four cycles are underway. ACT-1 (NCT00646854) includes ASCT consolidation and is directed at younger patients, whereas ACT-2 (NCT00725231) is directed at older patients but does not include ASCT consolidation. While intravenous alemtuzumab remains the treatment of first choice for TPLL, a typically chemo-refractory T-lymphoproliferative disease [80,85], safe delivery of 5.6

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5.5

Lenalidomide

Lenalidomide is a thalidomide analogue and is a standard agent in the treatment of multiple myeloma and myelodysplastic syndrome with deletion of 5q but appears to have modest antitumor effects across a broad range of malignancies. The mechanism of action is uncertain but is best understood in myeloma where it induces apoptosis via activation of caspases [68]. Other effects include inhibition of VEGF, and inhibition of multiple tumor-promoting and inflammatory cytokines including IL-1b, IL-12 and IL-6, which are associated with myeloma cell survival [68-70]. Lenalidomide is being actively developed as combination partner with rituximab for B-cell lymphoma where it is thought to enhance antibody-dependent cell-mediated cytotoxicity (ADCC) [71-75]. This is a well-tolerated oral medication, which has reversible, dose-dependent cytopenia as its principle side effect. Fatigue is moderately common. In patients with myeloma where it is frequently given with dexamethasone, it increases the risk of venous thromboembolism and thromboprophylaxis is therefore recommended. An interim report of the first part of a two-stage Phase-II study of lenalidomide as monotherapy for patients with T-cell lymphoma other than mycosis fungoides was published by Dueck et al. [76] and final results were presented at the ASH meeting, 2013 [77]. Thirty-nine patients with a median age of 65 were assessable; in 8 cases, lenalidomide was the first treatment delivered for PTCL. Patients were treated with 25 mg orally, D1-21, with dose reductions as appropriate. The overall response rate was 26% (10/39), of whom three patients achieved a CR. Three additional patients had stable disease for at least five cycles. Of those responding, the median PFS was 4 months (range < 1 -- > 50). The most common grade IV event was thrombocytopenia (21%), and grade III neutropenia occurred in 13%. In the interim publication, it was noted that six patients developed a skin rash and of those five developed a disease response, a clinical observation that supports a hypothesis that in this context lenalidomide has an immune-mediated mechanism of action. Zinzani reported a Phase II study of 10 patients treated with the same lenalidomide dosing strategy for PTCL [78]. Patients had received a median of four prior treatments and the response rate achieved was 30%, with three patients achieving a CR ranging in duration between 11 and 19 months and one, stable disease. Lenalidomide is under ongoing development in various investigator-initiated studies as a partner medication with other active biological treatments for PTCL, and we see this as its chief potential. It may also have potential as

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Table 4. Other drugs recently or soon to be developed for peripheral T-cell lymphomas. Drug Bortezomib Carfilzomib E7777

Ruxolitinib

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Sorafenib Zanolinumab

Notes Tested as combination partner with HDAC inhibitors Alternative proteasome inhibitor --Phase II study in PTCL underway A modified version of denileukin diftitox with improved purity and manufacturing process. Denileukin diftitox has orphan drug status for CTCL in the USA. Randomized studies are underway A JAK inhibitor currently undergoing Phase II testing for relapsed lymphoma in investigator-sponsored studies A multikinase with a single pilot study reporting CR in 4 of 12 patients with either CTCL or PTCL [96] Anti CD4 antibody with activity in PTCL. Development has focused on CTCL. The ORR was 24% in a 21 patient Phase II study in PTCL [97]

CTCL: Cutaneous T-cell lymphoma; HDAC: Histone deacetylase; ORR: Overall response rate; PTCL: Peripheral T-cell lymphoma.

alemtuzumab requires considerable supportive care resource and we remain skeptical about the feasibility and value of chemotherapy/alemtuzumab combinations for other forms of PTCL outside of a clinical trial. Mogamulizumab and antiviral therapy for ATL Mogamulizumab is a humanized anti-CCR4 antibody, which was initially developed as a treatment for ATL in Japan [86]. CCR4 is expressed in Th2 and T-regulatory cells and in ~ 90% of cases of ATL, two-thirds mycosis fungoides, and one-third of other T-cell lymphoma subtypes [86-88]. Mogamulizumab reduces tumor cell load through ADCC. A Phase II multi-centre trial [89] of weekly infusions demonstrated a response rate of half of 26 evaluable patients who had relapse/refractory ATL. The median progression-free time was 5.2 months and overall survival 13.7 months. The treatment is associated with infusion reaction in 90% of patients, usually on early treatment cycles. Skin rash is also common, and of interest as more severe rashes were associated with clinical response. In the first-line setting mogamulizumab may have a role. Initial results from a randomized Phase II study of combination chemotherapy with or without mogamulizumab demonstrated a higher CR rate in the experimental arm of 52% compared with 33% in the experimental arm [90]. More detailed results are awaited. A Phase II study in other forms of PTCL and CTCL was conducted in Japan and reported at the ASH meeting, 2012. CCR4-positive tumors were a requirement [91]. Mogamulizumab was delivered for eight infusions and produced an overall response rate of 35% and CR rate of 14%. Infusionrelated event occurred in 22%. Analysis of time-dependent endpoints and experience in a broader population of patients is awaited before the future role of this agent may be assessed. 5.7

Bendamustine Bendamustine is a nitrogen mustard which has alkylator and purine analogue activity, and it has an established role in the 5.8

208

treatment of low-grade B-cell lymphoma. In the BENTLY trial of 60 patients, predominantly with AILT or PTCL (NOS), patients were treated at a relatively high dose of 120 mg/m2 days 1 and 2 of a 21-day cycle [92]. This produced an overall response rate of 50% and CR in 28%; however, the median duration of response was short at 3.5 months. The toxicities were predominantly hematological. Bendamustine does not currently have marketing approval for PTCL. Future trials are exploring multi-agent combinations combining bendamustine with both novel therapy and other chemotherapeutic regimens, and it is our view that bendamustine is a promising combination partner. Alisertib Alisertib is a small molecule selective inhibitor of aurora A kinase. The kinase has increased expression in all dividing cells but in particular lymphoma [93]. This agent is currently being explored in over 30 clinical trials across a range of solid and hematological malignancies. Dose-finding studies were performed in solid tumors, and a Phase II study in NHL was performed on the basis of preclinical activity of the agent. In the study, 48 patients, 8 with T-cell lymphoma, were enrolled [93]. Alisertib was delivered orally twice daily for 7 days every 3 weeks. Treatment was continued until disease progression. The most common grade III/IV toxicities were neutropenia (63%), anemia (35%), thrombocytopenia (33%) and stomatitis (33.5%). Five of the eight PTCL patients had a partial response or better, and a further two had tumor shrinkage [93]. On the basis of these observations, a multi-centre international study of alisertib versus investigator choice of pralatrexate, gemcitabine or romidepsin for relapsed T-cell lymphoma (LUMIERE) is underway. It has a target recruitment of 354 patients, and the primary outcome measures are overall response and PFS. (NCT01 482962 clinicaltrials.gov) On the whole, this is a well-tolerated agent and so the outcome of these trials is highly anticipated. Other agents under active investigation are summarized in Table 4. 5.9

Expert Opin. Emerging Drugs (2014) 19(2)

Emerging drugs for T-cell lymphoma

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6.

Potential development issues

The three major advances in T-cell lymphoma have been with romidepsin, pralatrexate and brentuximab vedotin. Each is delivered as a long-term maintenance treatment, and each bring a degree of toxicity that may become less tolerable as cycles continue. Combinations with other agents would be expected to add to these toxicities and the threshold for market viability going forward will be the ability to substantially abbreviate treatment with the combination, without exorbitant financial or quality-of-life cost to patient. As we have discussed, the rarity and heterogeneity of these diseases results in slow trial recruitment and difficulty constructing trials of adequate power to demonstrate the survival advantage frequently demanded by regulatory authorities. 7.

Conclusion

Amongst the agents discussed, brentuximab vedotin stands out as a highly active and well-tolerated agent against its target population of patients with CD30+ ALCL. Other novel agents bring relatively short-term responses and benefit only a few. Genuine improvements of cure and survival rates are within the reach of the agents discussed here, but we will be waiting some time for the results of the large trials currently underway. 8.

Expert opinion

Declaration of interest

There is probably no room in the market place for all the agents discussed here and in Table 4. Romidepsin and pralatrexate are approved in the USA, but in the absence of randomized trials, more widespread approval will be challenging. Moreover, it will be a significant challenge to transition these two agents to first-line therapy. First, both romidepsin Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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M Dickinson has received research funding from Celgene, Novartis and Merck. He has been a consultant for Celgene, Novartis and Takeda/Millenium. M Prince has received research funding from Celgene, Novartis and Merck. He has been a consultant for Celgene, Novartis, Merck and Millenium.

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Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by Chulalongkorn University on 01/04/15 For personal use only.

Affiliation

Michael Dickinson† & Henry Miles Prince † Author for correspondence Peter MacCallum Cancer Centre and University of Melbourne, Division of Cancer Medicine, St Andrew’s Place, East Melbourne, Victoria, Australia Tel: +61 3 96561111; Fax: +61 3 86720774; E-mail: [email protected]

Expert Opin. Emerging Drugs (2014) 19(2)

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Emerging drugs for T-cell lymphoma.

T-cell lymphomas are rare and conventional treatments are not typically curative. Integration of biologic agents into routine practice is especially d...
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