Brentuximab vedotin (BV) is an antibody drug conjugate targeting the CD30 antigen. It employs a cleavable protease linking to a monomethyl auristatin E (MMAE) cytotoxic payload. It was 2011 when the first U.S. Food and Drug Administration (FDA) approvals occurred in relapsed/refractory Hodgkin lymphoma (HL) and relapsed/refractory CD30+ anaplastic large-cell lymphoma (ALCL). Single-agent response rates exceeded 75 percent in both settings. The next approval arrived in 2015 to be used as a single-agent maintenance strategy in high-risk HL post–autologous stem cell transplantation. In 2017 it was approved for use in relapsed cutaneous T-cell lymphoma and CD30+ mycosis fungoides. Then, in 2018, it was approved for use in frontline HL as part of the AAVD (adcetris, adriamycin, vinblastine, dacarbazine) regimen based on a modest progression-free survival (PFS) benefit when compared to ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). The HL trial leading to approval was called ESCHELON-1.
We now have a positive trial in CD30+ T-cell lymphoma called ESCHELON-2, which used a “repeal and replace” strategy, eliminating vincristine from the experimental regimen and substituting in BV. Patients with previously untreated CD30+ peripheral T-cell lymphoma (PTCL) were randomly assigned to treatment with BV, cyclophosphamide, doxorubicin, and prednisone (A+CHP) or to chemotherapy alone using cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). The patients received 21-day cycles of either regimen, with a BV dose of 1.8 mg/kg each cycle. A total of six or eight cycles were given at the investigators’ discretion.
A total of 452 patients were randomly assigned. A+CHP was superior to CHOP for the primary endpoint of PFS, with a median of 48.2 versus 20.8 month in the CHOP group (hazard ratio, 0.71; p=0.01). To put it another way, the three-year PFS for A+CHP was 57.1 percent, versus 44.4 percent for CHOP. A+CHP was also superior for overall survival with a hazard ratio of 0.66 (p=0.024). Rates of adverse events were similar between groups. Febrile neutropenia was seen in 18 percent of A+CHP patients and in 15 percent of the CHOP group, and peripheral neuropathy was observed in 52 percent and 55 percent of these patients, respectively.
Outcomes for patients with aggressive T-cell lymphomas have remained frustratingly inferior to those of their B-cell counterparts. There has been no rituximab equivalent to close the gap. However, with the completion of the ESCHELON-2 trial, it seems the gap will finally narrow for a subset of patients with T-cell lymphoma. In ESCHELON-2, 70 percent of patients enrolled had systemic anaplastic large cell lymphoma (sALCL), a T cell lymphoma defined by high expression of CD30. The benefit observed in the trial was large in this group of patients and seems to have driven the overall results. For patients with the much more common entity of PTCL-NOS and the less common entity of angioimmunoblastic T-cell lymphoma (AITL), which tend to have weak expression of CD30, there was no statistically significant benefit in PFS.
In Brief
In the trial, CD30+ was defined as more than 10 percent of cells by local review. Any case of sALCL will easily meet that threshold. Perhaps 50 to 60 percent of your PTCL-NOS and AITL will meet that threshold. So, should you use BV to treat any T-cell lymphoma with CD30+ features? My opinion is, no. I would definitely add BV to manage any case of sALCL. I find the data in PTCL-NOS and AITL unconvincing and believe more study is required to prove the benefit in these subtypes. However, BV did receive broad FDA approval for use in any CD30+ T-cell lymphoma. Whether one opts to use it in just sALCL or more broadly, it is clear we have achieved a major therapeutic advance in the frontline management of some T-cell lymphomas.
Competing Interests
Dr. Kahl has received consulting fees from Seattle Genetics.
