Peripheral T-Cell Lymphoma: New Therapeutic Strategies
Peripheral T-Cell Lymphoma: New Therapeutic Strategies
ABSTRACT: Between 2006 and 2011, four new agents gained regulatory approval for the treatment of relapsed/refractory cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL). These new approvals, together with recent advances in both combination chemotherapy and transplant strategies, have made the landscape for treatment of these patients immensely complex. Multiple clinical trials are now underway, evaluating the role of combining new agents with existing drugs and regimens, both for untreated and relapsed/refractory CTCL and PTCL. Pending results of such trials, clinicians are generally left with incomplete data and competing therapies when tasked with the treatment of these patients. In this article, we will briefly review the labeled indications for new agents for CTCL and PTCL, but will focus on data from the last 1 to 2 years, and on data from ongoing clinical trials, with the hope that in doing so we can help elucidate difficult treatment decisions.
Peripheral T-cell lymphoma (PTCL) is a diagnostic category that encompasses a broad range of diverse but rare mature lymphomas of T-cell origin. By convention, these are often divided into three clinical categories: nodal, extranodal, and leukemic. Some authorities also include a fourth category, the cutaneous variant (cutaneous T-cell lymphoma [CTCL]); others consider the staging, prognosis, and treatment of CTCL disparate enough to consider it a separate disease entity. (In practice, and for the sake of this review, we consider them separate entities.) Regardless of subtype, cases of PTCL share aggressive clinical behavior, refractoriness to conventional chemotherapy, and poor overall prognoses. An important exception, however, is anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALCL), a diagnosis that can carry a favorable prognosis in many patients.
Recent data suggest a significant increase in the US incidence of the most common types of PTCL.[3,4] While some of the increase may be the result of an aging population, it is also likely due to improved diagnostic techniques, particularly advances in immunohistochemistry (IHC). Unfortunately, no clear improvement in outcomes has been observed on a population scale, despite the fact that, since 2009, three new agents have been approved for the treatment of patients with relapsed/refractory PTCL (although it is perhaps too early to judge their effects). However, recent and planned trials continue to clarify the deployment of the new agents in this population, and trials aimed at approval for additional agents are underway. The purpose of this article is to briefly review the data from pivotal trials for those drugs approved for relapsed/refractory PTCL, focusing on recent data that inform more precise deployment of these agents, and to evaluate the early and ongoing data for novel combination and single-agent therapies.
Recently Approved Agents
A series of recent phase II, single-arm trials led to the approvals of three new drugs; what follows is a brief review of the efficacy and toxicity findings of those studies.
In 2006, the US Food and Drug Administration (FDA) approved the oral histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid) for the treatment of relapsed/refractory CTCL. The aceylation of histones is an important mechanism in the regulation of gene expression, and a large family of naturally occurring HDACs are responsible for the closure of chromatin, which results in transcriptional repression. Overexpression of various HDACs has been described in various solid tumors[6,7] and hematologic malignancies (including lymphoma),[8,9] and it is thought that the excess HDAC activity leads to repression of important tumor suppressor genes, permitting oncogenic cell growth and division. Vorinostat demonstrates potent and targeted inhibition of various HDAC isoforms. Its approval was based on the results of a single-arm trial of 74 patients with stage IB–IVA CTCL, treated with 400 mg by mouth daily until disease progression or intolerability. The overall response rate (ORR) was 30%, and the median duration of response (DOR) was over 6 months (not reached at time of reporting). Another phase II trial of 33 patients with similar disease characteristics demonstrated an ORR of 24% and a median DOR of 3.7 months.
The phase II PROPEL (Pralatrexate in Patients with Relapsed or Refractory Peripheral T-cell Lymphoma) trial was the first of its kind devoted to a population of patients with relapsed/refractory PTCL; it led to the approval of the anti-folate drug pralatrexate in 2009. In preclinical models, pralatrexate demonstrated superior intracellular penetration, polyglutamylation (which extends intracellular half-life), and inhibition of tumor growth, compared with either methotrexate or pemetrexed. In the PROPEL study, 115 patients with various PTCL histologic subtypes were treated at a dose of 30 mg/m2, in cycles consisting of weekly treatment for 6 weeks, followed by 1 week of rest. The ORR was 29%, with an 11% complete response (CR) rate. The median progression-free survival (PFS) and overall survival (OS) were 3.5 and 14.1 months, respectively. This population had a median of three prior systemic therapies, and common toxicities consisted of mucositis, thrombocytopenia, and neutropenia. Pralatrexate was also evaluated in a dose-escalation study of 54 patients with relapsed/refractory CTCL. The ORR for patients treated at between 15 and 30 mg/m2 for 3 weekly doses in 4-week cycles was 61%, with a median PFS of 13 months, but the investigators judged 15 mg/m2 to be the ideal dose for such patients, based on its risk/benefit ratio; this is the dose that was used for most of the patients (n = 29) included in the study. A recent report has suggested that pre-emptive leucovorin rescue can mitigate toxicity from pralatrexate while preserving efficacy, but further randomized studies (now planned) and longer follow-up are needed before this can be recommended as a standard method.
Also in 2009, the HDAC inhibitor romidepsin gained approval for both PTCL and CTCL in patients whose disease had failed at least one prior systemic therapy. Similar to vorinostat, romidepsin provides potent inhibition of HDAC isoforms, although response to the drug does not seem to correlate with the degree of observed HDAC inhibition, nor with increased acetylation or restored expression of any particular gene, hampering efforts to predict which patients are most likely to benefit from this agent. Two pivotal trials of romidepsin in patients with CTCL, involving a total of 167 patients, resulted in ORRs of 25% and 33%, with median DORs of 11 and 15 months, respectively.[18,19] Similar results were observed in PTCL, with one study of 47 patients showing an ORR of 38% and a median DOR of 9 months, and another study of 130 patients showing a lower ORR (25%) but a longer median DOR (17 months). The most common grade 3/4 toxicities were cytopenias and infections; however, remarkably high rates of nausea and fatigue/weakness (both primarily grade 1/2) were also observed.
In 2011, the FDA granted accelerated approval to the antibody-drug conjugate brentuximab vedotin, based on the results of two phase II trials, one in patients with relapsed/refractory classic Hodgkin lymphoma (cHL), and another in patients with relapsed/refractory ALCL. Brentuximab vedotin targets CD30, is endocytosed, and results in targeted delivery of the microtubule inhibitor monomethyl auristatin E. In patients with cHL, the ORR for brentuximab vedotin was 73%, with a median DOR of 7 months; in ALCL, the ORR was 86% and the median DOR was 13 months. Notably, in both trials, the patients who achieved a CR had a substantially longer median DOR than those who achieved a partial response (PR). The most common grade 3/4 toxicities were cytopenias; peripheral neuropathy occurred in over half of patients but was mostly sensory and primarily grade 1/2. There have been four cases of progressive multifocal leukoencephalopathy in patients receiving brentuximab vedotin, leading to a boxed warning. Rare cases of serious pancreatitis have also been reported in patients receiving the drug after its FDA approval. After the approval of brentuximab vedotin for cHL and ALCL, a phase II trial evaluating its safety and efficacy in relapsed/refractory PTCL (other than ALCL), irrespective of CD30 expression, was undertaken; preliminary results were presented in June 2013. Of the first 22 patients who were evaluable, 8 (36%) have demonstrated an objective response, with a seemingly higher response rate (50%) in the 10 patients with angioimmunoblastic T-cell lymphoma (AITL). Of particular note, and consistent with other early reports, response to brentuximab vedotin does not seem to correlate with CD30 expression, suggesting either the presence of off-target effect(s) or limitations to current IHC techniques with respect to this antigen.
Other Early-Phase Trials
The BELIEF trial is a phase II single-arm study of the HDAC inhibitor belinostat in patients with relapsed/refractory PTCL. The drug was given at a dose of 1,000 mg/m2 IV for 5 consecutive days in 21-day cycles. Patients were treated until progression or unacceptable toxicity, and the primary endpoint was ORR. A total of 129 patients were enrolled, and the first efficacy data were reported at the American Society of Clinical Oncology Annual Meeting in June 2013. The drug was well tolerated, with low rates of grade 3/4 toxicity. The ORR was 26%, including an 11% CR rate. Another HDAC inhibitor, panobinostat, has demonstrated significant activity in a phase II trial of patients with relapsed/refractory CTCL treated with a 20-mg dose on days 1, 3, and 5 of each week. In the 60 bexarotene-naive patients, the ORR was 20%, compared with 15% in the 79 patients who had already received bexarotene. The median PFS was approximately 4 months for both groups.
The immunomodulatory agent lenalidomide, which was approved for the treatment of multiple myeloma in 2005 and for mantle-cell lymphoma in 2013, was also studied in three phase II trials[31-33] of patients with relapsed/refractory PTCL. ORRs reported in these studies ranged between 22% and 30%, with a subset analysis of one study, suggesting that those patients with AITL enjoy a statistically nonsignificant trend toward improved response rates and PFS.
A phase I trial of the aurora kinase inhibitor alisertib demonstrated significant activity for this agent in the small subset of patients with relapsed/refractory PTCL. This has led to further investigation of alisertib as a single agent in a Southwest Oncology Group (SWOG) trial that completed enrollment in May 2013 (ClinicalTrials.gov identifier NCT01466881; efficacy data yet to be reported), and as part of an industry-sponsored phase III trial (ClinicalTrials.gov identifier NCT01482962) in which patients are randomly assigned to treatment with either alisertib or investigator’s choice of pralatrexate, romidepsin, or gemcitabine as single agents. Enrollment in this trial began in late 2012; no data have yet been reported.
Fenretinide is a synthetic retinoic acid that has also shown striking activity in a subset of patients with PTCL. A phase I trial that included patients with multiple types of relapsed/refractory hematologic malignancies demonstrated an ORR of 36%, with documented responses lasting 3 years in those patients with PTCL. A phase II trial focused on PTCL is planned, although enthusiasm for this drug is tempered by its delivery regimen (120-hr continuous infusion, every 21 days).
Anthracycline-based combination chemotherapy appears to remain the default backbone regimen for the exploration of new agents in the treatment of younger patients (generally under age 60 years), in spite of evidence suggesting that anthracyclines do not clearly improve outcomes for such patients. For example, a German cooperative group has reported their extensive experience using the combination of cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (CHOEP) in the treatment of patients with newly diagnosed PTCL. In their pooled analysis of newly diagnosed PTCL patients treated with anthracycline-containing regimens as part of prospective trials, event-free survival (EFS) was significantly longer for those who received etoposide as part of initial therapy (as part of CHOEP), although the improved EFS was due in part to the subset of patients with ALK-positive ALCL, in whom the difference in outcomes reached greatest significance.
Because anthracycline-based therapy remains the default standard of care for first-line treatment of PTCL, a number of trials are underway to evaluate combinations of novel agents with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and CHOP-like therapies. For instance, a large international trial (ClinicalTrials.gov identifier NCT01420679) is currently randomizing patients with untreated PTCL who achieve a response with CHOP to either observation or pralatrexate maintenance, administered until either intolerable adverse effects or progression of disease; no safety or efficacy data have yet been reported. The combination of romidepsin plus CHOP is also being actively explored. Results of a phase IB trial of 18 patients demonstrated that romidepsin can be safely administered at a dose of 12 mg/m2 on days 1 and 8, along with conventional CHOP (forming the so-called “RoCHOP” regimen) given on day 1 of 28-day cycles. The ORR in this study was 78%, with a CR rate of 66% and a 1-year PFS of 57%, all of which approximate historical outcomes with CHOP alone. Based on these data, a phase III international trial (goal accrual of 420) comparing RoCHOP with CHOP in patients with untreated PTCL, has begun enrolling patients (ClinicalTrials.gov identifier NCT01796002).
On the other hand, in an effort to obviate exposure to anthracyclines, a consortium of US investigators evaluated the regimen CEOP (cyclophosphamide, etoposide, vincristine, and prednisone) alternating with pralatrexate in a phase II trial of 34 patients with untreated PTCL. The regimen was reasonably well tolerated, although preliminary, unpublished results seem to indicate that response rates and rates of early progression are not clearly superior to those observed with CHOP (Dr. Julie Vose, personal communication). Nonetheless, this may eventually present a viable treatment option for patients in whom anthracyclines cannot be used, and formal presentation of the data is awaited.