Successful Treatment of Primary Cutaneous Anaplastic Large Cell Lymphoma with Denileukin Diftitox.

Primary cutaneous anaplastic large cell lymphoma (PCALCL) is a rare variant of cutaneous T cell lymphoma (CTCL) characterized by CD30-expressing large atypical cells with kidney-shaped nuclei called hallmark cells. Since PCALCL is a rare variant of CTCL, the treatment of PCALCL is still controversial. In this report, a case of PCALCL successfully treated with denileukin diftitox as second-line therapy is described. Interestingly, the administration of denileukin diftitox decreased CD8+ T cells, CD25+ cells, granulysin-bearing lymphocytes, and CD163+ macrophages. The present case suggests that denileukin diftitox might induce an anti-lymphoma effect as well as modulate the tumor microenvironment.

Introduction

Primary cutaneous anaplastic large cell lymphoma (PCALCL) is a variant of CD30+ lymphoproliferative disorders characterized by CD30-expressing large atypical cells [1]. Since PCALCL is a rare variant of cutaneous T cell lymphoma (CTCL), the treatment of PCALCL is still controversial, and there is no specific recommended therapy line for the treatment of PCALCL [2]. In this report, a case of PCALCL successfully treated with denileukin diftitox as second-line therapy is described.

Case Report

A 74-year-old Japanese man visited a private clinic with a 5-month history of red nodules on his extremities. On physical examination at his initial visit, multiple, elastic hard, red nodules were found on the breast, left femur, and left lower leg (Fig. 1a). A biopsy specimen from the left lower leg showed dense infiltration of atypical lymphocytes from the superficial to deep dermis without epidermotropism (Fig. 1b). These large atypical cells possessed twisted, kidney-shaped nuclei with small vesicles (Hallmark cells) (Fig. 1c).

Fig. 1

aMultiple, elastic hard, red nodules on the left femur and lower leg.bA biopsy specimen from the left lower leg shows dense infiltration of atypical lymphocytes from the superficial to deep dermis.cLarge atypical cells possess twisted kidney-shaped nuclei with small vesicles (Hallmark cells). d Immunohistochemical staining for CD30.

Immunohistochemical staining showed that these atypical lymphocytes were positive for CD3, CD4, CD7, and CD30 (Fig. 1d) and negative for CD5, CD8, CD20, CD79a, TIA-1, granzyme B, and anaplastic lymphoma kinase (ALK). A full blood count and biochemical profile were within normal ranges except for a slight increase of serum soluble IL-2R (721 U/mL). Positron emission tomography (PET) showed that there was no lymph node or visceral involvement. The diagnosis was CD30+ primary cutaneous anaplastic large cell lymphoma (PCALCL), and he was treated with oral bexarotene (300 mg/m2) with radiotherapy (30 Gy in 15 fractions). Since serum triglyceride levels were increased (1,073 mg/dL) after the administration of bexarotene (CTCAE ver. 4.0: G4) and since other multiple lesions developed on the face (Fig. 2a) and trunk (Fig. 2b), denileukin diftitox 9 μg/kg, 5 days in a row, was given every 3 weeks. The multiple nodules on the trunk gradually flattened (Fig. 2c, d), though he had liver dysfunction (CTCAE ver. 4.0: G3) with spontaneous remission on initial administration.

Fig. 2

Multiple lesions are seen on the face (a) and trunk (b) after the administration of bexarotene. Multiple nodules are seen on the trunk after the administration of denileukin diftitox (c,d).

Immunohistochemical Analysis of Lymphoma Infiltrating Cells

To investigate the immunomodulatory effects of denileukin diftitox, immunohistochemical staining of CD8 (Fig. 3a, b), CD25 (Fig. 3c, d), granulysin (Fig. 3e, f), CD161 (data not shown), and CD163 (Fig. 3g, h) was performed. The percentage of IHC-positive cells per all tumor-infiltrating cells was quantitatively analyzed by BZ-X800 (KEYENCE, Tokyo, Japan), as we previously reported [3]. The proportion of CD8+ cells, CD25+ cells, CD163+ macrophages, and granulysin-bearring cells among the leukocytes in the dermis was decreased after the administration of denileukin diftitox (Fig. 3i). Few CD161 positive cells were detected in the lesional skin of PCALCL.

Fig. 3

Immunohistochemical staining for CD8 (a,b), CD25 (c,d), granulysin (e,f), and CD163 (g,h) at baseline or 1 month after the administration of denileukin diftitox. Quantitative analysis of CD8+ cells, CD25, granulysin, and CD163+ cells: the IHC-positive cells within the lymphocyte fraction and the percentage of IHC-positive cells per all tumor-infiltrating cells were automatically counted using a BZ-X800 (i).

Discussion

PCALCL is a rare variant of CTCL characterized by CD30-expressing large atypical cells with kidney-shaped nuclei called hallmark cells [1]. Since a previous report suggested that multiagent chemotherapy such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) had no indications in CTCL as a first-line therapy because of its poor efficacy [4], these chemotherapy protocols were not recommended for the treatment of PCALCL. Another possible therapy for PCALCL is brentuximab vedotin (BV), which is an anti-CD30 monoclonal antibody conjugated to monomethyl auristatin E via a protease-cleavable linker; it is used for the treatment of CD30+ lymphomas such as PCALCL [5], but BV is not permitted by the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan for the treatment of PCALCL. For the above reasons, radiation therapy with oral administration of bexarotene, which was discontinued due to severe adverse events (hypertriglyceridemia), was selected as first-line therapy. Since there was a case report that described successful treatment of PCALCL by denileukin diftitox [6] and since phase II clinical study of denileukin diftitox contains 2 cases of PCALCL [7], we selected the denileukin diftitox as a second-line therapy.

Denileukin diftitox is a chimeric immunotoxin consisting of a fusion of the full-length human IL-2 protein with a modified cytotoxic domain of diphtheria toxin that was approved for use for advanced CTCL by PMDA in 2021 [8]. Its overall response rate (ORR) for advanced-stage CTCL was 44% (44/100), and the median progression-free survival (PFS) was over 2 years [9]. Although the incidences of severe adverse events (SAEs) were 34% in the denileukin diftitox arm, incidences of treatment-related SAEs were 4% (4/100) [9], suggesting that denileukin diftitox was well-tolerated for the treatment of advanced CTCL.

From the above findings, denileukin diftitox was given as second-line therapy for PCALCL. Interestingly, the administration of denileukin diftitox decreased the CD25+ cells as well as CD8+ cells, granulysin-bearing lymphocytes and CD163+ macrophages. Since Tregs highly express CD25 on its surface [10], and since Tregs maintain the M2 polarization of TAMs through PD-L1/PD1 signaling [11], denileukin diftitox might repolarize to an M1 phenotype and induce an anti-tumor immune response in the lesional skin of PCALCL. Indeed, quantitative analysis suggested the decrease of CD163+ M2 macrophages. This report presents only a single case, but further cases may provide fundamental insights into the mechanisms of the immunomodulatory effects of denileukin diftitox in advanced CTCL.

Statement of Ethics

Written, informed consent was obtained from the patient for publication of this case report and any accompanying images. The protocol for this human study was approved by the Ethics Committee of Tohoku University Graduate School of Medicine, Sendai, Japan (permit no. 2021-1-1213).

Conflict of Interest Statement

The authors have no conflicting interests to declare.

Funding Sources

This study was supported in part by a grant-in-aid for scientific research from the Japan Society for the Promotion of Science (21K08318). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author Contributions

Mayuko Amagai, Sadanori Furudate, Kentaro Ohuchi, Toshiya Takahashi, Emi Yamazaki, Hiromu Chiba, and Taku Fujimura treated the patient and acquired the clinical data. Mayuko Amagai and Taku Fujimura wrote the manuscript. Yoshihide Asano and Taku Fujimura supervised the study.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.