Research in context
Evidence before this study
We searched the scientific literature to identify reports of patients with cutaneous T-cell lymphoma, Sézary syndrome, and KIR3DL2. We searched Medline for studies published in English from Jan 1, 1990, to Dec 31, 2018. Search items included “cutaneous T-cell lymphoma”, “KIR3DL2”, and “Sézary syndrome”. Cutaneous T-cell lymphoma is an uncommon and incurable form of non-Hodgkin lymphoma. Sézary syndrome accounts for around 5–10% of cutaneous T-cell lymphomas and is the leukaemic and most aggressive form, with median survival rarely exceeding 4 years. Affected patients typically have severe pruritus, frequent infections, and body disfigurement resulting in poor quality of life. In 2018, two novel drugs, brentuximab vedotin and mogamulizumab, were approved for the treatment of subsets of patients with cutaneous T-cell lymphoma who received at least one previous systemic therapy. However, patients with Sézary syndrome were included only in the trial of mogamulizumab. In more refractory patients (ie, those who have received at least two prior systemic therapies), no drugs are proven to be effective in patients with Sézary syndrome. Vorinostat is the only approved agent in the USA, which in a phase 3 trial showed an overall response of 2% in patients with Sézary syndrome. KIR3DL2 (CD158k) is a member of the highly polymorphic family of killer-cell immunoglobulin-like receptors and is widely expressed in cutaneous T-cell lymphoma, and in more than 85% of patients with Sézary syndrome, and was proposed as the most sensitive diagnostic and prognostic marker for these patients.
Added value of this study
To our knowledge, this study is the first reported trial of the anti-KIR3DL2 antibody IPH4102. We report activity of this novel, targeted drug in a rare form of cutaneous T-cell lymphoma, Sézary syndrome, with a high unmet medical need. Unlike previous studies of drugs in patients with refractory cutaneous T-cell lymphoma who received at least two previous systemic therapies, this study used the international consensus response criteria. This study shows high activity of IPH4102 in patients with Sézary syndrome who received at least two previous systemic therapies. The treatment was well tolerated with no identified dose-limiting toxicity. These results represent a potential new treatment for patients with refractory Sézary syndrome.
Implications of all the available evidence
On the basis of our results, IPH4102 received fast-track designation from the US Food and Drug Administration for the treatment of adult patients with relapsed or refractory Sézary syndrome who have received at least two prior systemic therapies. A multi-cohort phase 2 trial (TELLOMAK) is underway to confirm the activity in patients with Sézary syndrome and explore the role of IPH4102 in other subtypes of T-cell lymphomas that express KIR3DL2.