Peripheral T-Cell Lymphoma: Time for a T-Cell–Centric Standard of Care

Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of rare and aggressive lymphomas that comprise about 12% of all lymphomas.[1] The low incidence and heterogeneity of these lymphomas are compounded by the lack of standardized treatment options for them.[2,3] First-line therapies for PTCL have commonly been extrapolated from treatments for aggressive non-Hodgkin B-cell lymphomas; however, patients with PTCL have inferior responses to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based regimens.[2-5] Anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALCL) has a relatively good prognosis [6]; the prognosis for most other subtypes of PTCL is significantly inferior to that of B-cell lymphoma.[3,5-7] The causes of this are multifactorial; primary among them are the paucity of T-cell–specific chemotherapy platforms, and the fact that much remains unknown regarding the biology of T-cell lymphoma. A few studies suggest improved outcomes with more dose-intense chemotherapy regimens (such as hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone [hyper-CVAD] alternating with high-dose methotrexate and high-dose cytarabine; or etoposide, ifosfamide, and cisplatin alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine [VIP-rABVD]), but these regimens do not offer substantial additional benefits over CHOP, and these benefits are at the cost of greater toxicity.[7,8] The landscape may be changing, however; in the past 5 years, 4 new drugs have been approved for the treatment of PTCL.

In this issue of ONCOLOGY, Drs. Petrich and Rosen present a thoughtful and comprehensive review of the landscape for PTCL in 2013, addressing the newly approved agents for relapsed/refractory disease, as well as novel therapies and platforms currently under investigation.[9] Their review highlights the challenges of developing therapies for a disease that affects few patients and for which there is an abundance of promising emerging treatments.

The approval of 4 new drugs in 5 years for a lymphoma with no previous disease-specific standard of care represents a major scientific and clinical advance-yet one of the consequences of the orphan disease status of PTCL is that the bar for approval by the US Food and Drug Administration has been quite low. The agents that have been approved have, in general, demonstrated a modest overall response rate (ORR) of about 20% to 30% and a duration of response (DOR) of 3 to 9 months; the exception is brentuximab vedotin, which has an ORR of 86% and a DOR of 13 months in ALCL patients.[10-13] Going forward, the challenge is to improve this modest single-agent response rate by developing rational combinations with nonoverlapping toxicities. Petrich and Rosen discuss the strategy of combining the new agents with CHOP or CHOP-like therapies, with attention to ongoing clinical trials investigating those combinations. However, given that CHOP is derived from therapy for B-cell lymphomas, and given the profusion of novel T-cell–focused agents, the time may be at hand to design novel CHOP-free T-cell–centric treatment platforms both for first-line therapy and for relapsed disease.

This may take some time, given the rarity and heterogeneity of PTCL. It has been observed that different subtypes of PTCL respond differently to particular therapies.[2,3,6] For example, as discussed in Petrich and Rosen’s review, angioimmunoblastic T-cell lymphoma (AITL) demonstrated a superior ORR and DOR with the histone deacetylase inhibitor belinostat compared with the ORR and DOR seen in other subtypes of PTCL. Mogamulizumab, an anti-chemokine receptor 4 (CCR4) antibody that recently obtained regulatory approval in Japan, is currently under investigation in adult T-cell leukemia/lymphoma (ATLL) based on the biology of ATLL, which is known to have high CCR4 expression.[14] The heterogeneity of PTCL presents challenges for determining treatment strategies that incorporate these biological differences; as suggested by our experience to date with brentuximab, belinostat, and mogamulizumab, it is more likely that specific individual therapies will be targeted to specific PTCL subtypes than that a single one-size-fits-all strategy will be adopted. Given the rarity of many of these PTCL subtypes, communication between bench and bedside is vital to elucidate disease biology, which may guide the clinician in the rational use of these novel therapies. This successful crosstalk between basic, clinical, and translational science ideally will be bidirectional, as therapies move from bench to bedside in the clinical trial phase of development, and as the correlatives from these clinical studies further deepen our understanding of disease biology and suggest rationales for possible therapeutic combinations.

To speed the pace of the development of new therapies, enhanced participation in clinical trials is key. Given that no clear first-line strategy exists, and that the therapies for relapsed and refractory disease do not result in sustained responses for many patients, eligible PTCL patients should be encouraged to participate in investigational studies. This enhanced participation may catalyze scientific advances for these rare lymphomas. Petrich and Rosen mention a Danish-based study in which only a small minority of eligible patients with PTCL have participated. This issue exists in the United States as well; a recent US study revealed that only 9% of cancer patients participate in clinical investigations, with various factors-such as older age, lower economic status, and lower education level-hindering participation.[15] Addressing these barriers is vitally important.

This is an exciting time in the treatment of PTCL, but with this opportunity comes responsibility. The challenge of how to optimize a plethora of promising new therapies for a small number of patients will drive therapeutic decision making for the foreseeable future. Ultimately, the goal is to develop therapies with high clinical efficacy and minimal toxicity, that are effective across many PTCL subtypes. To whatever degree this is accomplished, it will be important to clarify which therapies are effective for which patients, so that patients are not treated with ineffective therapies, and also so that treatments that are highly effective in only a narrow range of PTCL subtypes are tested appropriately and not mistakenly abandoned. This translational approach will hopefully change the future landscape of PTCL, offering effective therapies and improved survival for the patients suffering from this disease.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

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