New promising targets and targeted drugs for treatment of aggressive forms of systemic mastocytosis are few; in this issue of Blood, Blatt et al1  provide evidence that aberrant Ki-1 antigen (CD30) expression on neoplastic mast cells may serve as a therapeutic target of brentuximab-vedotin alone or in combination with KIT-targeting drugs.

CD30 is an established therapeutic target of the CD30-targeting antibody-drug conjugate brentuximab-vedotin in patients with Hodgkin lymphoma2  and anaplastic large cell lymphoma.3  Recent reports have also demonstrated brentuximab-vedotin efficacy in relapsed/refractory diffuse large B-cell lymphoma4  and primary effusion lymphoma.5  Valent and colleagues have recently shown that CD30 is aberrantly expressed in the cytoplasm of neoplastic mast cells in patients with advanced systemic mastocytosis (SM).6  In the current study, the authors asked whether CD30 is expressed on the surface of neoplastic mast cells in advanced systemic mastocytosis and whether this surface structure may serve as a therapeutic target in mastocytosis. The authors found that CD30 is expressed on the surface of neoplastic mast cells in 3/25 patients (12%) with indolent SM (ISM), 4/7 patients (57%) with aggressive SM (ASM) and 4/7 patients (57%) with mast cell leukemia (MCL). The immature RAS-transformed human mast cell line MCPV-1.1 also expressed cell surface CD30, whereas the KIT-transformed human mast cell line HMC-1.2 expressed no detectable CD30. In most patients, CD30 expression in mast cells was confirmed by immunohistochemistry on bone marrow sections. Using flow cytometric analysis, the authors demonstrated a correlation between the type of systemic mastocytosis and the surface CD30 expression on mast cells. CD30 levels on mast cells in patients with advanced disease (ASM and MCL) were higher than in ISM patients (median CD30 MFI: ASM/MCL 4.24 vs ISM 1.88, P < .05).

Further experiments showed downregulation of cell surface CD30 expression and CD30 messenger RNA levels by mitogen-activated protein kinase kinase (MEK) inhibitors PD032509 and RDEA119 in CD30+ mast cell lines, suggesting that expression of CD30 in neoplastic mast cells is regulated by a RAS-MEK–dependent signaling pathway. The authors then proceeded to measure serum levels of soluble CD30 (sCD30) in mast cell patients. Results revealed an increase in serum levels of sCD30 in advanced SM compared with ISM. The highest levels of sCD30 were measured in patients with ASM or MCL, with a median of 129.0 ng/mL, compared with a median of 21.0 ng/mL in ISM patients.

Prior reports demonstrated that CD30-targeting antibody-drug conjugate brentuximab-vedotin inhibits the growth of CD30+ lymphoma cells.7,8  In the current study, Blatt et al showed that brentuximab-vedotin inhibited proliferation of neoplastic mast cells. Lower 50% inhibitory concentration values were obtained in CD30+ mast cell line MCPV-1.1 (10 μg/mL) compared with CD30 HMC-1.2 cells (>50 μg/mL). Brentuximab-vedotin produced a G2/M cell cycle arrest in CD30+ cell lines MCPV-1.1 and C2 and at high concentrations in CD30 low-expressing HMC-1.1 cells. In contrast, brentuximab-vedotin did not induce a cell-cycle arrest in CD30 cell lines HMC-1.2 and MCPV-1.4. In addition, brentuximab-vedotin produced apoptosis in all CD30+ mast cell lines tested as well as in primary neoplastic mast cells in patients with CD30+ SM, but not in neoplastic mast cells in patients with CD30SM. The concentrations of brentuximab-vedotin required to inhibit proliferation in primary neoplastic mast cells and CD30+ mast cell lines corresponded well with drug concentrations that can be reached in patients treated with this drug.9  By contrast, the CD30 mast cell lines that were examined showed only a weak response or did not respond at all. Furthermore, the authors confirmed the growth-inhibitory effect of brentuximab-vedotin in an in vivo xenotransplantation assays showing that brentuximab-vedotin suppressed engraftment of CD30+ MCPV-1.1 cells in nonobese-severe combined immunodeficiency interleukin-2Rγnull mice.

Patients with advanced systemic mastocytosis not only suffer from the consequences of mast cell proliferation in various organs, but also from symptoms caused by the mediator release from activated neoplastic mast cells. The authors tested whether brentuximab-vedotin treatment triggered histamine release, which is important for assessment of future potential for severe reactions during therapy. Brentuximab-vedotin was found to downregulate anti-immunoglobulin E–induced histamine release in CD30+ mast cells, whereas no effect of brentuximab-vedotin on histamine release was seen in CD30 mast cells. Also, no substantial effects of brentuximab-vedotin on immunoglobulin E–mediated upregulation of CD63 or CD203c on basophils or CD30+ mast cell lines were seen.

Most patients with ASM or MCL show clinically meaningful and sometimes even complete responses to KIT D816V-targeting drug midostaurin (PKC412).10  However, responses are usually short-lived. Therefore, there is a need for novel potent, targeted drugs that can elicit synergistic growth-inhibitory effects when combined with PKC412. In this study, Blatt et al demonstrated that brentuximab-vedotin and midostaurin (PKC412) produced synergistic growth-inhibitory effects in CD30+ mast cell line MCPV-1.1. Based on these data, it seems tempting to propose a clinical trial exploring anti-neoplastic effects of the drug combination PKC412 and brentuximab-vedotin in advanced systemic mastocytosis.

Overall, this is a very exciting study that points to the Ki-1 antigen (CD30) as a promising new drug target for patients with advanced systemic mastocytosis. The data presented in this study show that antineoplastic effects of brentuximab-vedotin are largely dependent on the surface expression of CD30, suggesting the need for routine testing for CD30 surface expression on neoplastic mast cells by flow cytometry. In the future, CD30 expression on mast cells may serve as a potentially valuable screening tool, prognostic marker, and therapeutic target in advanced forms of mast cell disease that currently represent a treatment challenge with poor prognosis.

Conflict-of interest disclosure: The author declares no competing financial interests.

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