Wei Z. Ai, MD
Cutaneous T-cell lymphoma (CTCL) is known to be a rare malignancy, with approximately 3000 diagnoses per year. Historically, progress in developing therapies for this form of non-Hodgkin lymphoma (NHL) has been slow, but 2017 brought about the FDA approval of brentuximab vedotin (Adcetris), giving hope to this poor-prognosis population.
Brentuximab vedotin was approved in November 2017 as a treatment for patients with CTCL who have received prior systemic therapy, specifically for patients with primary cutaneous anaplastic large cell lymphoma and CD30-expressing mycosis fungoides—the most common subtypes of CTCL.
The approval was based on findings from the phase III ALCANZA trial, in which brentuximab vedotin induced a response lasting at least 4 months in 56.3% of patients. This is in comparison with the 12.5% response rate seen with the comparator of physician’s choice.1
The anti-CCR4 monoclonal antibody mogamulizumab was granted a priority review designation to a biologics license application for the treatment of patients with CTCL who have received at least 1 prior systemic therapy. This application was based on data of the phase III MAVORIC study, which was presented at the 2017 ASH Annual Meeting. Data from this study showed that mogamulizumab reduced the risk of progression or death by 47% compared with vorinostat (Zolinza) in pretreated patients.2
The investigator-assessed median progression-free survival was 7.7 months (95% CI, 5.7-10.3) in the mogamulizumab arm compared with 3.1 months (95% CI, 2.9-4.1) in the vorinostat arm (HR, 0.53; 95% CI, 0.41-0.69; P <.0001), and the overall response rate was 28% with mogamulizumab versus 4.8% with vorinostat (P <.0001).
Wei Z. Ai, MD, an associate clinical professor and hematologist at the University of California, San Francisco (UCSF) Medical Center, gave a presentation on recent developments in T-cell lymphoma during the 2017 OncLive® State of the Science SummitTM on Hematologic Malignancies. In an interview during the meeting, Ai discussed the impact of brentuximab vedotin, as well as the potential with mogamulizumab in CTCL.
OncLive: What recent data have we seen in this space?
: In systemic T-cell lymphoma, there were no practice-changing trials presented [at the 2017 ASH Annual Meeting]. However, we are hoping for results from some exciting phase I/II trials in 2018. Phase III trials based on those trials are ongoing, and may be practice changing.
As for CTCL, 2017 was a very exciting year. In the history of this disease, there have only been about 3 randomized studies as it is such a rare disease with only 3000 new cases a year. The first one was in the 1980s, which showed sequential single-agent therapy is as good as combination agents. This is why we treat these patients very differently than the systemic T-cell lymphoma where we almost always use combinations. Two phase III studies were presented at the 2017 ASH Annual Meeting, one of which contributed to the approval of brentuximab vedotin in CTCL about 1 month prior to its presentation at the meeting. The third phase III study of mogamulizumab for CTCL will hopefully lead to an approval very soon; the FDA has granted it a breakthrough designation.
How has the approval of brentuximab vedotin impacted clinical practice thus far?
In my experience, this is a highly active drug, particularly in the advanced-stage disease. CTCL is a very heterogeneous disease; 75% present with early-stage disease and only 25% present with advanced-stage disease. Therefore, as oncologists, we are going to see the patients who are much sicker than the average patients with CTCL.
For early-stage disease, patients receive skin-directed therapy that is often managed by a dermatologist. For advanced-stage disease, patients require system therapy. However, the way that systemic therapy is given to these patients is very different than in systemic T-cell lymphomas. At UCSF, we are very fortunate to have a multidisciplinary clinic where we have dermatologists and radiation oncologists.
Advanced-staged CTCL is a life-threatening disease; the median survival is 2 to 5 years. People don't realize that because it is so rare. I see brentuximab vedotin in the scenario where this disease is life threatening—in tumor-stage and widespread disease—and I've seen patients with visceral disease respond nicely to this drug. If you look at the randomized trial of brentuximab vedotin and physician's choice very carefully, you can see the dramatic superiority of brentuximab, particularly in the advanced stage of disease.
Can you speak to the data that we have seen with mogamulizumab?
It is an active drug that is pretty well tolerated, particular in Sézary syndrome, as it clears the blood very quickly. Sézary syndrome is a leukemic form of CTCL which, from our historical data, has a median survival of about 5 years. Patients [with Sézary syndrome] quickly grow resistant to chemotherapy.
We have biologic therapies for that disease, but there are a proportion of patients who will progress on that and require a type of chemotherapy. Those patients acquire resistance quite quickly, unfortunately. Therefore, mogamulizumab is very active in this setting and we will use it a lot.
What could the potential impact of mogamulizumab be if approved by the FDA?
When patients with CTCL are in the advanced stage of their disease and require systemic therapy, there is the possibility for acquired resistance. This drug is so well tolerated; it is really going to change the management of advanced-stage disease. The most use will probably be in Sézary syndrome, as it is an advanced stage of disease and is life threatening. The most commonly used therapy at the moment is extracorporeal photopheresis, which is only available in a few academic centers.
Is there anything else you would like to add?
CTCL is an extremely rare form of T-cell lymphoma, and [therapeutic] options would very much benefit the field. We get a lot of referrals from the community, and we feel that the co-management of this population is very important. We would like to continue to do that and, hopefully, we can make the patients’ lives better.
- Kim YH, Whittaker S, Horwitz SM, et al. Brentuximab vedotin demonstrates significantly superior clinical outcomes in patients with CD30-expressing cutaneous T cell lymphoma versus physician's choice (methotrexate or bexarotene): the phase 3 ALCANZA study. Presented at: 58th Annual ASH Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract 182.
- Kim YH, MD, Bagot M, Pinter-Brown L et al. Anti-CCR4 monoclonal antibody, mogamulizumab, demonstrates significant improvement in PFS compared to vorinostat in patients with previously treated cutaneous T-Cell lymphoma (CTCL): results from the phase III MAVORIC study. In: Proceedings from the 2017 ASH Annual Meeting; December 9-12, 2017; Atlanta, Georgia. Abstract 817.