Associate Attending Physician
Department of Medicine
Memorial Sloan Kettering Cancer Center
Associate Professor of Medicine
Weill-Cornell Medical Center
New York, New York
The ECHELON 2 Trial
Peripheral T-cell lymphoma (PTCL) is a rare and aggressive form of non-Hodgkin lymphoma with a standard first-line treatment of combination chemotherapy regimens such as CHOP and similar combination multi-drug regimens. However, complete and durable responses are too infrequent even when consolidation with high dose therapy and autologous stem cell transplantation is added. New and more effective therapies are needed. My colleagues and I presented data at the 2018 ASH meeting from the phase III ECHELON 2 study adding brentuximab vedotin to frontline chemotherapy in newly diagnosed patients with CD30-positive PTCL. The results of this study have quickly and significantly impacted how we are taking care of our patients with PTCL.
ECHELON 2 was a double-blind, randomized study enrolling patients with CD30‑positive PTCL (N = 452) who were randomized to receive either brentuximab vedotin plus CHP with placebo in place of vincristine or to standard CHOP with placebo in place of brentuximab vedotin.
With a median follow up of 36.2 months, study results showed a significant improvement in PFS for patients in the intent-to-treat population treated with brentuximab vedotin plus CHP of 48.2 months compared with 20.8 months for those treated with CHOP (HR: 0.71; 95% CI: 0.54-0.93, P = .0110). This translated into an OS benefit as well, with a 34% reduction in the risk of death for patients receiving brentuximab vedotin plus CHP. Toxicity overall, and in particular rates of neuropathy and neutropenia, were similar between the two arms. Prior to ECHELON 2, there were no randomized studies that showed such a compelling PFS or event‑free survival benefit in this setting, and there were certainly no studies that showed an OS benefit, so these results have immediate clinical impact.
How I Use Brentuximab Vedotin for PTCL in My Practice
When I consider how to apply these data in the clinic, I mostly refer to the ECHELON-2 eligibility criteria. Patients in this study were required to have CD30‑positive PTCL, defined as at least 10% of the tumor cell population expressing CD30. The majority of patients in the study (70%) had either ALK-positive anaplastic large cell lymphoma (ALCL) with additional risk factors or with ALK‑negative ALCL. For patients with systemic ALCL, this data strongly, and in my practice unequivocally, supports adding brentuximab vedotin to frontline treatment as a standard therapy.
The other subtypes such as PTCL not otherwise specified (PTCL-NOS) or angioimmunoblastic T-cell lymphoma (AITL), with variable and lower incidence of CD30 expression than those with ALCL, made up 30% of the total and were not powered to asses outcomes independently. Given that the ITT populations showed an OS benefit and in these patients the HRs (although not statistically significant) were 0.83 and 0.87, respectively, although not statistically significant, the use of brentuximab vedotin plus CHP should be considered for these patients.
The use of BV-CHP in non-ALCL subtypes may also be weighed against other existing data. The other commonly used alternative to CHOP for PTCL is CHOEP (CHOP plus etoposide). The data supporting CHOEP as possibly superior to CHOP comes from a PTCL subset analysis of a series of prospective studies from Germany comparing CHOP to etoposide-containing regimens. In these studies, CHOEP led to an event free survival benefit without an improvement in overall survival in younger patients. Older patients (age >60) had excess toxicity when etoposide was added. As in ECHELON-2, the majority of patients in the German study also had ALCL (66%), with a subset of patients having PTCL-NOS or AITL (34%). While either approach may be superior to CHOP alone, the CHOEP study was not a double blinded, randomized study, did not have an OS benefit, and adding etoposide did result in some increased toxicity.
In patients with AITL,PTCL-NOS, ALK‑negative ALCL, and occasionally those with high-risk, AL-positive ALCL, the other approach I have often considered and used is to consolidate therapy after initial remission with high‑dose chemotherapy and autologous stem cell transplantation. This question has come up a lot with ECHELON-2: Does it affect the need for transplantation? A minority of patients in the study received transplantations, but patients in either study arm could have been transplanted, so we do not have any data yet to say that an appropriately high‑risk patient can do just as well without receiving consolidation therapy and autologous transplantation. This is a question that will require further research.
My key takeaway from ECHELON-2: Brentuximab vedotin plus CHP is an optimal induction regimen for patients with untreated PTCL and CD30 expression, and I have adopted this regimen, in the absence of an appropriate clinical trial, as a preferred treatment strategy for these patients. Consolidation with transplant remains an appropriate strategy for fit high‑risk patients, even if they receive brentuximab vedotin as part of their induction therapy.
What are your thoughts on brentuximab vedotin plus CHP in PTCL? Let me know in the comments below.
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