Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project

Abstract

Purpose: In contrast to Hodgkin lymphoma and systemic anaplastic large-cell lymphoma, CD30 expression of malignant lymphocytes in mycosis fungoides (MF) and Sézary syndrome (SS) is quite variable. Clinical activity and safety of brentuximab vedotin, a CD30 targeting antibody-drug conjugate, was evaluated in MF and SS. Tissue and blood biomarkers of clinical response were explored.

Patients and methods: In this phase II study, patients with MF or SS with negligible to 100% CD30 expression levels were treated with brentuximab vedotin (1.8 mg/kg) every 3 weeks for a maximum of sixteen doses. The primary end point was overall global response rate. Secondary end points included correlation of tissue CD30 expression level with clinical response, time to response, duration of response, progression-free and event-free survivals, and safety.

Results: Of the 32 patients enrolled and treated, 30 patients had available efficacy evaluations. Objective global response was observed in 21 (70%) of 30 patients (90% CI, 53% to 83%). CD30 expression assessed by immunohistochemistry was highly variable, with a median CD30max of 13% (range, 0% to 100%). Those with <5% CD30 expression had a lower likelihood of global response than did those with 5% or greater CD30 expression (P < .005). CD163 positive tumor-associated macrophages, many of which coexpress CD30, were abundant in tissue. Peripheral neuropathy was the most common adverse event.

Conclusion: Brentuximab vedotin demonstrated significant clinical activity in treatment-refractory or advanced MF or SS with a wide range of CD30 expression levels. Additional biomarker studies may help optimize rational design of combination therapies with brentuximab vedotin.

Trial registration: ClinicalTrials.gov NCT01396070.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

© 2015 by American Society of Clinical Oncology.

Figures

Fig 1.

Clinical presentation of the patients at baseline and with brentuximab vedotin treatment. (A) 66-year-old woman with mycosis fungoides (MF) stage IVB with oral disease; the patient had a maximum reduction in modified Severity-Weighted Assessment Tool score from time of screening (mSWATmax) of 86%. (B) 87-year-old man with MF stage IIB with ulcerative tumor on the arm; the patient had an mSWATmax reduction of 92%. (C) 66-year-old man with MF stage IIB with forehead tumor; the patient had an mSWATmax reduction of 97%. (D) 78-year-old woman with Sézary syndrome (SS) stage IVA1; the patient had an mSWATmax reduction of 100% (global complete response). (E) 80-year-old woman with SS stage IVA1; the patient had an mSWATmax reduction of 89%; flow cytometry showing reduction of CD4+/CD26-/CD30+ Sézary population after treatment. (F) 45-year-old man with MF IVA2 with reduction in lymph-node disease after treatment, as shown in the positron emission tomography-computed tomography scan.

Fig 2.

Primary study end-point analyses. (A) Maximum change in modified Severity Weighted Assessment Tool (mSWAT) score (skin disease burden) compared with baseline in all patients treated with brentuximab vedotin (n = 30). Eight patients had more than 90% reduction in their mSWAT score, including one complete response (stage IV/SS) and seven near complete responses, including two stage IB (patch/plaque only) and five stage IIB (patch-plaque and tumor). Clinically meaningful responses were seen in both tumor and patch-plaque lesions. Horizontal line at −50% indicates the threshold for defining partial response in the skin. (*) Patients with stage IV (extracutaneous) disease. Overall global response was determined by composite of skin, lymph node, viscera, and blood compartment responses. (B) Time course in patients who had global clinical responses to brentuximab vedotin (n = 21). (C) Progression-free survival (n = 32). (D) Event-free survival (n = 32), with event defined as toxicity-related termination, progressive disease, death, or start of another systemic therapy. BV, brentuximab vedotin.

Fig 3.

Maximum change in modified Severity Weighted Assessment Tool (mSWAT) by tissue CD30max (maximum level of CD30 expression) assessed by immunohistochemistry, stratified by disease stage and global clinical response. Data support a correlation between skin CD30max and depth of skin response (reduction in mSWAT; P = .0031).The dotted line depicts CD30max of 5%. Patients with CD30max of < 5% had a significantly lower likelihood of clinical response (P = .0046).

Fig 4.

Multispectral imaging (MSI) analysis of CD30 expression. (A) Clinical photograph of a patient at the time of screening. Immunohistochemistry (IHC) stain of the highlighted biopsy site showed CD30 level of 0% as assessed by conventional light microscopy (LM). (B) MSI series of a representative CD30 immunostained area from the same biopsy. The MSI system converts the standard light microscopic image into a pseudo-colored composite: the counterstain is shown in the pseudo color blue, and the CD30 is represented by the pseudo color red. The composite image can be unmixed into single components, counterstain and CD30. The CD30 panel highlights the CD30 stain in pseudo color red. (C) Histogram showing optical density (OD) values per cell in biopsy. Each bar represents the average OD value of an individual cell (n = 207 cells). Nonspecific background OD (0.02, including two stable disease) was subtracted from all values, and any bar therefore signifies specific CD30 staining. The visibility threshold indicates the OD below which CD30 stain was undetectable by visual inspection with conventional LM but positive by MSI analysis. (D) CD30 and CD163 double-stained lesional skin: conventional LM image of CD30 (light pink) and CD163 (brown) double stain. Here, the areas that exceed the nonspecific background OD for CD30 are shown in red, thus the color red depicts CD30 positivity. CD163+ cells are shown in green. The areas of spatial colocalization of both stains are highlighted in gold, demonstrating the extent of CD30 and CD163 coexpression in this lesion. (E) CD30 and CD8 double-stained lesional skin from the same subject: conventional LM image, showing CD30 (light pink) and CD8 (brown). Corresponding MSI of CD30+ (red) and CD8+ (green) cells and the coexpression of both markers (gold) in this area.

Fig A1.

Study design. CR, complete response; EOT, end of treatment; IHC, immunohistochemistry; MF, mycosis fungoides; PD, progressive disease; PR, partial response; SS, Sézary syndrome.