Clinical Remission of Cutaneous Lymphoma in a Dog Treated with Verdinexor
ABSTRACT
A 5 yr old female spayed pit bull terrier mix was evaluated for development of multiple dermal nodules over the previous 2 wk with concurrent weight loss and lethargy. A definitive diagnosis of cutaneous epitheliotropic T-cell lymphoma was obtained through histopathology and immunohistochemistry. Treatment was initiated with 32.9 mg/m2 (1.2 mg/kg) of oral verdinexor twice per week, according to label guidance. One week after treatment initiation, clinical remission was noted with complete resolution of the cutaneous nodules. The dog has continued twice-weekly treatments without any interruption and remains in complete remission 17 mo following initiation of verdinexor therapy. This case provides evidence for the utility of verdinexor in the treatment of canine cutaneous epitheliotropic T-cell lymphoma.
Introduction
Cutaneous epitheliotropic T-cell lymphoma (CETL) is an uncommon form of lymphoma in dogs, constituting only 3–8% of all canine lymphomas. CETL is characterized by the infiltration of neoplastic lymphocytes into the epithelium, and these lymphocytes are typically CD8+ T cells. Diagnosis can be made by cytology in some cases; however, histopathological examination of a skin biopsy is required for definitive diagnosis and to assess for evidence of epitheliotropism. The prognosis for dogs with CETL is poor, with reported mean survival times ranging from only a few months to 2 yr.1
Several drugs and treatment protocols have been used to treat CETL, none of which have clearly demonstrated high efficacy. Lomustine is currently regarded as the best treatment option for CETL and is often the first-line chemotherapeutic to be used.1 A retrospective study of 46 cases of CETL in a 15 yr interval treated with lomustine found a response rate of 83% with complete remission achieved in 15 dogs (33%). The overall median duration of response was 94 days with a range of 22–282 days in dogs with complete and partial responses. Five dogs achieved stable disease with treatment and had a median time to disease progression of 60 days. Median survival time was not reported.2
A more recent retrospective study documenting outcomes of 176 dogs with CETL also found significant variability in survival time, ranging from 1 to 1178 days, with an overall median survival time of only 96 days from time of diagnosis. In this study, dogs were treated with a range of protocols including cytotoxic chemotherapeutics, small molecule inhibitors, antibiotics, steroids, and/or radiation, reflecting the therapeutic challenges associated with this cancer. Of the treated dogs, 27% achieved complete remission, 13% achieved partial remission, and 43% were classified as nonresponders. Time to disease progression was not reported in this study.3
In the case reported here, verdinexora was used for the treatment of CETL. Verdinexor is an orally bioavailable selective inhibitor of nuclear export. It works by inhibiting the actions of XPO1, a protein responsible for nuclear export, thus blocking the transport of several proteins involved in tumor cell growth from the cell nucleus to the cytoplasm. XPO1 inhibition results in retention of key proteins within the nucleus (i.e., tumor suppressor proteins such as p53 among others) that ultimately induces cell cycle arrest and apoptosis. In several cancers, XPO1 is overexpressed, resulting in a differential effect of its inhibition on the tumor cells compared with normal cells.4
Verdinexor has conditional licensure from the Food and Drug Administration since 2021 for the treatment of canine lymphoma, based on data generated from a phase 2 clinical trial. In this setting, dogs with naive and relapsed B-cell and T-cell multicentric/non-Hodgkin lymphoma were treated with verdinexor as a single agent. The objective response rate in dogs with multicentric T-cell lymphoma was only 10%, and the overall progression-free survival times were relatively short (less than 2 mo).4 The most common adverse effects reported with verdinexor were loss of appetite, gastrointestinal upset, and lethargy.5 The side-effect profile of selinexor, a similar medication in humans, includes lethargy and gastrointestinal upset, with thrombocytopenia, hyponatremia, neutropenia and anemia also reported in some patients. In this human study, treatment-related adverse events were most commonly classified as grade 1 or 2 and manageable with supportive therapies. Major organ toxicity was rare.6 To the authors’ knowledge, there have been no previous studies published regarding the efficacy of verdinexor in the setting of canine extranodal lymphoma.
Case Report
A 5 yr old spayed female pit bull terrier mix presented for evaluation of multiple round, haired, dermal nodules ranging from 2 to 13 mm in diameter on the head, neck, trunk, and pelvic regions (Figures 1A, B) that had developed rapidly over the previous 2 wk. During this time, the dog had developed anorexia and lethargy, resulting in weight loss. Other than the dermal masses and mild pododermatitis, the remaining physical examination was unremarkable with no peripheral lymphadenopathy. A month before this visit, a solitary dermal mass had been removed from the same dog’s dorsal neck region, which was diagnosed by histopathology as a cutaneous histiocytoma. Recovery from this procedure was uneventful, and the surgical site healed without any issues. Medications included cyclosporineb, prednisone, and monthly lokivetmabc injections to treat chronic atopic dermatitis. The patient has been receiving these medications at the same dosages for 1 yr prior, and her atopic skin disease has been stable with only mild flares during this time.
Citation: Journal of the American Animal Hospital Association 60, 5; 10.5326/JAAHA-MS-7443
A complete blood count and serum biochemistry were performed, and a mild elevation of the liver enzymes, likely secondary to chronic corticosteroid use, was the only notable abnormality (Table 1). Cytologic examination of fine-needle aspiration samples from masses on the head and trunk were consistent with a round cell neoplasm. Aspiration cytology of the superficial cervical lymph node demonstrated a reactive population of immune cells with no evidence of neoplasia. Three-view chest radiographs were unremarkable, whereas abdominal radiographs demonstrated mild splenomegaly. Consistent with this, point-of-care abdominal ultrasound confirmed mild splenic enlargement but normal echotexture and shape with no other abnormalities noted. Cytologic examination of splenic fine-needle aspiration samples revealed normal to mildly reactive splenic lymphoid tissue with no evidence of round cell neoplasia. Based on the histopathology of the previously removed mass and the presence of multiple cutaneous lesions, cutaneous histiocytosis was favored as the primary cytologic differential. The dog was then started on oral doxycycline (5 mg/kg q 12 hr) and oral niacinamide (25 mg/kg q 24 hr) to treat the suspected cutaneous histiocytosis.
On recheck examination 1 wk later, the dog exhibited continued weight loss, and there was no evidence of response to the prescribed treatment regimen. At this time, marginal excision of two dermal masses was undertaken to obtain a definitive diagnosis. Histopathologic examination of the biopsy samples demonstrated a nonencapsulated, highly cellular round cell neoplasm with infiltration into the dermis and subcutaneous tissues, with cells arranged in sheets and nodules oriented on adnexal structures. The cells had moderate amounts of pale eosinophilic cytoplasm with round to oval nuclei that were often indented with finely stippled chromatin and prominent nucleoli. There was marked anisokaryosis and anisocytosis with binucleate neoplastic cells (Figures 2A, B). There were 26 mitotic figures per ten 2.37 mm2 fields. Immunohistochemistry was performed to further characterize the neoplastic cells, revealing strong immunoreactivity for CD3, CD18, and Thy-1 but no expression of E-cadherin. As these cells were forming multifocal nests in the epithelium, this neoplasm was classified as CETL.
Citation: Journal of the American Animal Hospital Association 60, 5; 10.5326/JAAHA-MS-7443
Given the diagnosis of CETL, the doxycycline and niacinamide were discontinued. Prednisone, cyclosporine, and lokivetmab were continued to manage the dog’s atopic dermatitis, and treatment with verdinexor at 32.9 mg/m2 (1.2 mg/kg) orally twice weekly was initiated. Although contraindicated with malignancy, cyclosporine was continued in this patient owing to the severity of dermatologic disease and quality-of-life concerns when not receiving this medication. After 1 wk (two doses of verdinexor), the owner reported that the dog seemed to be feeling better and was gaining weight and that the masses had completely regressed. Over the next 6 mo of treatment, the dog gained weight, necessitating an increase in the total dose of verdinexor administered to maintain the label dosage of 1.2 mg/kg. No further dose escalation was instituted as the dog remained in complete remission and experienced mild side effects including inappetence and intermittent vomiting. These adverse events were well controlled with the concurrent oral administration of maropitantd as needed. Complete blood count and chemistry were monitored every 2 to 3 mo during treatment and were unremarkable except for mild to moderate waxing and waning liver enzyme elevations, consistent with chronic corticosteroid use (Table 1). The dog remains in clinical remission (Figure 1C) 17 mo into treatment at the time of writing this report and is currently doing well with no verdinexor-associated adverse events. Informed consent was obtained from the pet’s owners, and the patient was managed according to contemporary standards.
Discussion
This is the first case report to demonstrate the successful treatment of CETL in a dog with verdinexor. The response of this patient was both rapid, with resolution of skin lesions after just 1 wk of treatment, and prolonged, with the patient obtaining complete clinical remission for at least 17 mo with minimal side effects. This is in contrast to studies of various treatment protocols for CETL in dogs, including lomustine, which reported median response duration and survival time of only 94 and 96 days, respectively.2,3
Although verdinexor has previously been shown to have efficacy against canine multicentric/non-Hodgkin lymphoma as a single-agent treatment, it has not yet been reported in the treatment of canine CETL or other canine extranodal lymphomas.4 However, a recent report in human medicine documented efficacy of selinexor (a closely related XPO1 inhibitor) in human natural killer/T-cell lymphoma, a rare type of non-Hodgkin lymphoma with an extremely poor clinical outcome. In this study, five patients with severe cases of relapsed/refractory NK/T-cell lymphoma that had failed prior l-asparaginase and anti–PD-1 antibody were treated with at least one cycle of selinexor plus the same anti–PD-1 antibody. Of these, three had complete responses to therapy, and one patient had a partial response to therapy, with a median overall survival time of 12 mo, which is remarkable considering the aggressive nature of this disease.7
This case report suggests that verdinexor may be a promising new therapeutic option for canine CETL, a cancer that has historically carried a poor prognosis, with the majority of patients experiencing short survival times with the available treatments.1 Future prospective studies would provide further information regarding biologic activity in a larger population of dogs, as well as long-term tolerability of drug administration.
Conclusion
This is the first reported use of verdinexor in the successful clinical treatment of canine CETL. The patient experienced a sustained complete remission of greater than 17 mo with twice-weekly treatment, and the drug was well tolerated. Although further research is needed to understand the efficacy of this drug in a larger population of dogs with CETL or other extranodal lymphomas, clinicians may consider the use of verdinexor in the treatment of canine CETL.
The authors thank Dr. Cheryl London for her careful review of and contributions to this report.
Images of a 5 yr old spayed female pit bull terrier presenting for evaluation of multiple dermal nodules, shown here on the head (A) and trunk (B) before treatment with verdinexor. The same dog is pictured in complete remission after 12 months of twice-weekly treatment with oral verdinexor (C).
Photomicrographs of one of the dermal masses from the dog in Figure 1 viewed at ×20 magnification (bar = 20 μm) (A) and ×40 magnification (bar = 50 μm) (B). The dermis is expanded and infiltrated by round neoplastic cells. Multiple nests of neoplastic cells invade the epidermis. Hematoxylin and eosin stain.
Contributor Notes
