Previously obscured within other designations of aggressive lymphomas, peripheral T-cell lymphoma (PTCL) now represents 23 different subtypes of non-Hodgkin lymphoma (NHL). Despite the many subtypes now recognized, PTCL represents only approximately 10% of all NHL cases diagnosed. Positron emission tomography/computed tomography has become essential to accurate staging and response-evaluation for PTCL. In comparison to aggressive B-cell NHL, patients with PTCL will more often be refractory to initial therapy, and chemosensitive patients will have shorter disease-free periods. Anthracycline-based regimens, often with the inclusion of etoposide, are commonly used during induction therapy. Consolidation with high-dose therapy and autologous stem cell transplantation (ASCT) in first chemosensitive remission appears to provide the best outcome in common nodal PTCL subtypes. The commonly defined nodal subtypes are PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic lymphoma kinase (ALK)-positive or ALK-negative anaplastic large-cell lymphoma (ALCL). Four agents have been approved by the US Food and Drug Administration for use in the relapsed/refractory (rel/ref) setting, including belinostat (2014), romidepsin (2011), brentuximab vedotin (2011), and pralatrexate (2009). Brentuximab vedotin was approved only for the ALCL subtype. These agents continue to be studied as combinations in the rel/ref setting and as additions or substitutions for other agents in upfront multiagent chemotherapy regimens. Patients who have responded to treatment in the rel/ref setting and are considered transplant-eligible should be considered for allogeneic stem cell transplantation, especially those with previous ASCT. Upfront allogeneic stem cell transplantation remains a research question in the majority of PTCL subtypes, but data are emerging.
Twenty-three different variations of peripheral T-cell lymphoma (PTCL) have been defined by the 2008 World Health Organization classification. There have been significant strides in the attempt to improve the diagnostic accuracy of the approximately 6,000 cases of PTCL diagnosed each year in the United States.
Diagnostic accuracy has been enhanced by the use of expanded immunohistochemistry assessment, occasional pathognomonic cytogenetic results, and molecular studies. However, molecular evaluations other than T-cell receptor clonality studies have yet to translate to significant clinical application. With increased availability of positron emission tomography/computed tomography (PET/CT), the staging or extent-of-disease evaluation for patients with PTCL has become more essential and reliable, leaving localized or early-stage PTCL as an uncommon clinical scenario without a definitive standard of care. Once a diagnosis of PTCL is rendered, the stage is confirmed, and prognostic index variables are documented, an initial treatment regimen must be chosen.[2,3] Although the management landscape in PTCL is rapidly evolving, a few aspects are generally agreed upon: (1) a diagnosis of systemic PTCL (excluding cutaneous T-cell lymphoma) requires multiagent chemotherapy in order to be considered on a curative pathway; (2) clinical trial enrollment is paramount at any phase of care; and (3) in under a decade, four agents have been approved by the US Food and Drug Administration (FDA) for rel/ref PTCL. Beyond these basic agreements, the approach to diagnosis becomes more opaque, clinical outcomes are often statistically underpowered, case reports become more common, and prospective studies are scarce—that is, the grayscale of care becomes visible. This article evaluates the most up-to-date peer-reviewed published work on the treatment of PTCL, and offers a glimpse into the current upfront clinical trial landscape for patients affected by this uncommon disease—one that, it is hoped, will usher in a new or expanded era of management in PTCL.
The Future of Induction Therapy in PTCL: You’ve Been CHOPped
Progress in the treatment of PTCL has been gaining momentum, but breaking away from models of aggressive B-cell lymphoma has been a challenge. It is acknowledged that CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) was borrowed from the treatment of B-cell non-Hodgkin lymphoma (NHL) as an option for induction therapy in patients with PTCL. However, historic data in PTCL remain relevant compared with the majority of the data that preceded the rituximab era in the management of B-cell NHL. A large prospective trial of CHOP alone as induction therapy is not available in PTCL outside of an adult T-cell lymphoma/leukemia (ATLL) study in Japan. To set the stage in PTCL, the BC [British Columbia] Cancer Agency (BCCA) and German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) retrospective series provided a baseline against which to measure outcomes in PTCL going forward.[6,7] The BCCA report on 191 patients with PTCL demonstrated that patients with anaplastic lymphoma kinase (ALK)-negative anaplastic large-cell lymphoma (ALCL) and angioimmunoblastic T-cell lymphoma (AITL) had similar 5-year overall survival (OS) rates of 34% and 36%, respectively.
In the peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) cohort, the 5-year progression-free survival (PFS) and OS rates were 29% and 35%, respectively. The second series completed by the DSHNHL included 320 patients with PTCL from eight prospective trials. Adults < 60 years of age and those with a normal lactate dehydrogenase level at presentation had a worse outcome with CHOP alone vs CHOP plus etoposide (CHOEP). Of note, ALCL patients with the ALK-positive subtype benefited most from addition of etoposide. CHOEP was felt to be too toxic for patients over age 60, and its use should be considered on a case-by-case basis for this age group. These studies serve as historic baselines for future comparison of therapies in this setting.
Subsequently, research by the Nordic Lymphoma Group ushered in an era of prospective data with CHOEP in patients less than 60 years of age for whom consolidation with autologous stem cell transplantation (ASCT) was planned. Treatment with CHOEP yielded a complete response (CR) in 63% of patients and an overall response rate (ORR) of 82% by CT-based response criteria. PET/CT was not used to determine response in this study. Arguably, given these results it can be concluded that CHOEP is an efficacious approach, particularly in patients younger than 60 years of age who are considering a consolidation transplant approach. CHOP remains an option for patients who are over age 60 or believed to be unable to tolerate CHOEP.
Use of dose-adjusted (DA)-EPOCH (etoposide, cyclophosphamide, doxorubicin, vincristine, and prednisone), a continuous infusion–based regimen, is an option based on National Comprehensive Cancer Network (NCCN) guidelines. Results of DA-EPOCH in the upfront setting in common PTCL subtypes have yet to be published in a peer-reviewed journal, but a significant body of clinical experience and research is available in the medical literature regarding its use in aggressive B-cell NHL. The economic impact of DA-EPOCH is likely to be greater than that of CHOP/CHOEP in PTCL, as many institutions still require a 5-day inpatient stay for completion of the continuous-
Alemtuzumab, a CD52 antibody, plus CHOP (AL-CHOP) has been found to yield a high ORR of 90% but a short median event-free survival time of 10 months. However, significant concerns have been expressed regarding the risk of infectious death with this regimen. Furthermore, Corradini et al reported an age-adapted approach with alemtuzumab (30 mg for patients younger than 60 years of age; 10 mg for patients 60 years of age or older) in combination with CHOP. In patients 60 years or older, the intent was to administer 6 cycles of AL-CHOP. Among the patients evaluable for response, the CR rate was 72% with a 4-year OS of 31%. Alemtuzumab has also been studied as a maintenance approach post induction therapy with CHOEP, where etoposide was excluded for patients over age 60 by the DSHNHL group. A CR or very good partial response (VGPR) to CHOEP was seen in 33 of 41 patients (80.5%). (VGPR is not a recognized response criterion in the recently updated Lugano Classification response criteria.) A total of 29 of 41 patients went on to receive alemtuzumab maintenance. Interestingly, the 3-year OS rate among those treated with alemtuzumab was 75%, and most patients received the intended doses. In the alemtuzumab cohort, significant infectious toxicities were noted, and possibly one treatment-related death. The authors concluded that despite the results reported, the maintenance concept has been abandoned in favor of inclusion of alemtuzumab during induction therapy to possibly prevent early progression in patients over age 60. The younger cohort (patients < 60 years old) received only 2 cycles of AL-CHOP prior to transition to a higher-intensity regimen and subsequently ASCT or allogeneic stem cell transplant, based on donor availability. The ORR was 62% in this cohort. These results do not appear to be practice-changing, especially in the cohort of patients over 60 years of age. The use of alemtuzumab in PTCL has not gained much traction in the induction or rel/ref setting in North America.
In a retrospective fashion, the International Peripheral T-Cell Lymphoma Project reported the outcomes of 1,314 patients with PTCL. Interestingly, patients treated with anthracycline-containing regimens did not necessarily have better outcomes compared with those who received non-anthracycline regimens. This series did not discuss why certain patients did not receive an anthracycline-based regimen. Given these results and the unsatisfactory results with CHOP alone, non-anthracycline regimens have been explored. The first prospective study of a non-anthracycline regimen evaluated the PEGS regimen (cisplatin, etoposide, gemcitabine, and methylprednisolone). Among newly diagnosed patients only (as the study allowed relapsed patients later), the PEGS regimen demonstrated an ORR of 39% and a 2-year PFS rate of 14%. In the United Kingdom, CHEMO-T (ClinicalTrials.gov ID: NCT01719835), a phase II study, is using a similar non-anthracycline combination with cisplatin, gemcitabine, and methylprednisolone (GEM-P); study results have not yet been reported. Lastly, the non–anthracycline-based regimen CEOP (cyclophosphamide, etoposide, vincristine, and prednisone), alternating with pralatrexate (P), was tested in 33 patients in a phase II study by the North American Peripheral T-Cell Lymphoma Consortium; in their most recent update of the data, CEOP-P resulted in a CR rate of 52%, an ORR of 70%, and 64% OS at 2 years. Unfortunately, the prespecified endpoint was not met in this study, and it is uncertain whether this regimen will be assessed further in a randomized phase III study.
Accrual into new studies continues, in an attempt to improve outcomes by combining CHOP with novel agents, despite noncomparative prospective data on combination therapy including CHOEP. The use of novel agents in combination with CHOEP is also likely to be explored (Table 1). Brentuximab vedotin, a monomethyl auristatin E (MMAE) antibody conjugate directed at CD30 that is approved for the treatment of rel/ref ALCL, is the first novel agent for which early data on combination treatment for PTCL are available. In addition, a phase I study evaluated brentuximab vedotin combined with cyclophosphamide, doxorubicin, and prednisone (CHP) in newly diagnosed patients with CD30-positive PTCL; the reported CR rate was 88% and the estimated 1-year PFS rate was 71%. As a result of these strong findings, brentuximab vedotin plus CHP has bypassed traditional phase II testing and is the subject of a randomized phase III study (ClinicalTrials.gov ID: NCT01777152) in newly diagnosed CD30-expressing PTCL, with the control arm being CHOP.
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