奥拉替尼治疗犬皮肤趋上皮T细胞淋巴瘤：病例报告

王帆

Treatment of canine cutaneous epitheliotropic T-cell lymphoma with oclacitinib: a case report

奥拉替尼治疗犬皮肤趋上皮T细胞淋巴瘤：病例报告

作者：Jeylan Aslan，Michael A. Shipstone and Louise M. Sullivan

翻译：叶精精

Canine cutaneous epitheliotropic T-cell lymphoma (CETL) is associated with a poor prognosis and without consistently beneficial treatment options. This case report describes a 9-year-old Staffordshire bull terrier with CETL treated with oclacitinib (0.7 mg/kg twice daily), resulting in partial remission that was maintained for three months. Further studies are warranted.

摘要 – 犬皮肤趋上皮T细胞淋巴瘤(CETL)是预后不良，且无一致有效的治疗方案。本病例报告描述了1只9岁患CETL的斯塔福牛头㹴，接受了奥拉替尼（0.7 mg/kg，每日两次）治疗，可见部分缓解，并维持3个月。此方案需要进一步研究。

Introduction

介绍

Cutaneous epitheliotropic T-cell lymphoma (CETL) represents <1% of canine skin tumours.The prognosis is generally poor, with mean survival times reported from a few months to two years. Numerous treatment protocols have been reported including lomustine (CCNU), masitinib, polyethylene glycol (PEG)ylated L-asparaginase, PEGylated liposomal doxorubicin, retinoids, prednisolone, surgery and radiation. Single-agent chemotherapy with CCNU commonly is recommended, yet this requires regular monitoring for drug toxicity and results in complete remission in only 30% of cases for a median duration of 132 days (range 26–258 days) and a median survival time of six months after diagnosis. The numerous treatment protocols and lack of standardised treatment reflect the unpredictable response to treatment and generally poor outcome of this disease.

皮肤趋上皮T细胞淋巴瘤(CETL)在犬皮肤肿瘤中的占＜1%。预后一般较差，报道的平均生存时间为数月至两年。已经报道了许多治疗方案，包括洛莫司汀(CCNU)、马赛替尼、L-门冬酰胺酶、PEG化脂质多柔比星、维甲酸、泼尼松龙、手术和放疗。通常推荐CCNU单药化疗，但这需要定期监测药物毒性，只有30%的病例得到完全缓解，平均生存期为132天（范围26-258天），确诊后中位生存期为6个月。众多治疗方案,缺乏标准化治疗方案预示了该疾病反应多样性和预后不良。

Case report

病例报告

A 9-year-old male neutered Staffordshire bull terrier presented with a six month history of pruritus, scaling and ulcerative skin lesions. The dog had been treated with a 2% miconazole/2% chlorhexidine shampoo (Malaseb, Dermcare Vet; Slacks Creek, QLD, Australia) for a number of months. Cephalexin (Kefvet, Pharmachem; Eagle Farm, QLD, Australia), 23 mg/kg twice daily, and oclacitinib (Apoquel, Zoetis; Sydney, Australia), 0.7 mg/kg twice daily, were commenced two days before referral. At presentation the dog was lethargic and depressed. Dermatological examination showed generalised marked scaling and erythroderma with multifocal areas of alopecia and crusting, and multifocal erosion to ulceration of the face, distal limbs, perineum, groin and chest (Figure 1a–c). Skin cytological examination revealed degenerate neutrophils, lymphocytes and low numbers of coccoid bacteria. Six 6 mm punch biopsy samples were obtained under sedation and local anaesthesia for histopathological examination, fungal culture and aerobic bacterial culture. Treatment with cephalexin and oclacitinib was continued while awaiting the pathological results.

一只9岁的雄性已去势斯塔福牛头㹴因最近6个月的瘙痒、皮屑和溃疡性皮肤病变就诊。已接受2%咪康唑/2%氯己定香波治疗数月。转诊前2天开始口服头孢氨苄23 mg/kg每日两次，和奥拉替尼0.7 mg/kg每日两次。就诊时，该犬表现嗜睡和抑郁。皮肤体格检查：全身明显皮屑、皮肤发红，多灶性脱毛和结痂，面部、四肢远端、会阴、腹股沟及胸部多灶性糜烂至溃疡病变（图1a-c）。皮肤细胞学检查提示退行性中性粒细胞、淋巴细胞和少量球菌。在镇静和局部麻醉下采6个6 mm活检样本，进行组织病理学检查、真菌培养和需氧细菌培养。在等待病理学结果的同时，继续使用头孢氨苄和奥拉替尼治疗。

Figure 1. Clinical presentation of a Staffordshire bull terrier with cutaneous epitheliotropic T-cell lymphoma (CETL). Day 2 (a–c): Marked scaling to crusting with multifocal alopecia of the dorsum (a), and multifocal to coalescing areas of erosion to ulceration of the groin, medial thighs and perineum (b, c). Generalised erythroderma is not apparent due to medetomidine sedation. Day 23 (d–f): Marked improvement following treatment with oclacitinib.

图1.患有皮肤趋上皮T细胞淋巴瘤(CETL)的斯塔福牛头㹴的临床表现。第2天(a-c)：背部明显皮屑结痂和多灶性脱毛(a)，腹股沟、大腿内侧和会阴聚集型多灶性糜烂和溃疡区域(b，c)。由于美托咪定镇静作用，全身性皮肤发红不明显。第23天(d–f)：奥拉替尼治疗后显著改善。

Bacterial culture revealed Staphylococcus pseudintermedius and Enterococcus faecalis. Fungal culture was negative. Histopathological evaluation confirmed secondary bacterial pyoderma and extensive infiltration of the epidermis and adnexal epithelium by neoplastic CD3+ T lymphocytes, with occasional Pautrier’s microabscesses and multifocal dermal extension, consistent with CETL (Figures 2 and 3a,b). By Day (D)4 after commencement of cephalexin and oclacitinib the owner reported significant improvement in the dog’s demeanour, pruritus and appearance. Examination on D14 showed regression of approximately 80% of lesions with resolution of many of the areas of ulceration and moderate scaling of the dorsum. By D23 there had been further improvement with a single area of crusting and ulceration remaining, and mild scaling on the dorsum (Figure 1d–f). Seven 6 mm punch biopsies were taken from these areas. Histopathological examination revealed an estimated average of >80% reduction in neoplastic lymphocyte numbers across evaluated regions (Figures 2 and 3c,d), and resolution of the bacterial pyoderma. Complete blood count showed no significant abnormalities. Cephalexin was discontinued on D30. By D90 deterioration with erosion and increased scale was seen, despite continued administration of oclacitinib at 0.7 mg/kg twice daily. Treatment continued and on D115 the owner elected to euthanise the dog as a result of progressive lethargy and recurrence of ulcerative skin lesions.

细菌培养结果为假中间型葡萄球菌、粪肠球菌。真菌培养阴性。组织病理学评价证实继发细菌性脓皮病，表皮及附件上皮细胞被肿瘤性CD3+ T淋巴细胞广泛浸润，偶见Pautrier微脓肿和多处延伸至真皮，与CETL一致（图2和3a，b）。头孢氨苄和奥拉替尼给药后第4天，犬主人描述犬的行为、瘙痒和外观显著改善。第14天复查，约80%的病变消退，许多溃疡区域消退，背部中度皮屑。到第23天时，病情进一步改善，有单个结痂和溃疡区域，背部轻度皮屑（图1d–f）。在这些区域采7个6 mm样本活检。组织病理学检查显示，在不同区域的肿瘤淋巴细胞数量减少平均大于80%(图2和3c，d)，细菌性脓皮病消退。全血细胞计数未见明显异常。在第30天停用头孢氨苄。第90天，尽管继续每日两次给予奥拉替尼0.7 mg/kg，但仍观察到恶化，糜烂和皮屑增加。继续治疗，在第115天，由于进一步嗜睡和复发的溃疡性皮肤病变，犬主人选择对犬实施安乐死。

Figure 2. Representative histopathological findings of biopsies from a Staffordshire bull terrier with cutaneous epitheliotropic T-cell lymphoma (CETL). Day 2 (a,b): The epidermis and adnexal epithelium are extensively infiltrated by neoplastic lymphocytes, which also extend into the surrounding dermis and are accompanied by occasional Pautrier’s microabscesses (long arrow). Other changes detected included parakeratosis (short arrows) and regions of ulceration and serocellular crust, sometimes containing intralesional bacterial cocci (not illustrated). Day 23 (c,d): There is a marked reduction in the number and extent of infiltrating neoplastic lymphocytes within the epidermis, adnexal epithelium and dermis, with these images representing one of the more severe regions of remnant disease. Other changes noted include widespread superficial dermal fibrosis (asterisks) and irregular epidermal hyperplasia, this time with lamellar orthokeratosis (arrowheads). Haematoxylin & eosin. Scale bars: (a, c) 100 µm; (b, d) 50 µm.

图2：患有皮肤趋上皮T细胞淋巴瘤(CETL)的斯坦福牛头㹴活检的代表性组织病理学结果。第2天(a，b)：表皮和附件上皮细胞被肿瘤性淋巴细胞广泛浸润，也延伸至周围真皮，并偶尔伴有Pautrier微脓肿（长箭头）。检测到的其他变化包括角化不全（短箭头）以及溃疡和血清结痂区域，有时含有病灶内球菌（未显示）。第23天(c，d)：表皮、附件上皮细胞和真皮内浸润的肿瘤性淋巴细胞的数量和范围明显减少，这些图像为剩余病变中较严重区域。观察到的其他变化包括广泛的浅表真皮纤维化（星号）和不规则的表皮增生，这次伴有片状正角化性角化不全病（箭头）。苏木精和伊红染色。比例尺：(a，c)100µm；(b，d)50µm。

Discussion

讨论

Oclacitinib is a Janus kinase 1 (JAK1) inhibitor marketed for treatment of allergic pruritus in dogs. Although it is selective for JAK1, it also inhibits JAK2, JAK3 and TYK2.The JAK/STAT pathways are essential for T-cell function, and oclacitinib has been shown to deplete canine CD4+ and CD8+ T cells, and cause apoptosis of CD4+ and CD8+ T cells in vitro.  It also has been shown to inhibit canine T-cell proliferation and cytokine production in vitro, yet this was only severe and significant at a concentration corresponding to an oral dose of 3–4 mg/kg twice daily and did not appear to be significant at the usual therapeutic concentration. In humans, alterations in JAK/STAT signalling have been described in most T-cell lymphoproliferative disorders including CETL.These alterations include both gain-of-function mutations and activation in the absence of specific mutations. The cytokine interleukin (IL)-15 signals through JAK1 and JAK3, is an autocrine and paracrine growth and viability factor for neoplastic T cells, and may be involved in epidermotropism in CETL. Ruxolitinib, a JAK1/2 inhibitor, is approved for treatment of myeloproliferative neoplasms in humans, and preliminary results from an ongoing clinical trial in human CETL patients has shown positive outcomes, with a greater and more durable response in patients with documented JAK/STAT alterations.

奥拉替尼是一种Janus激酶1(JAK1)抑制剂，上市用于治疗犬过敏性瘙痒症。尽管其对JAK1具有选择性，但也可抑制JAK2、JAK3和TYK2。JAK/STAT通路对T细胞功能至关重要，已证明奥拉替尼在体外可大量消耗犬CD4 + 和CD8 + T细胞，并引起CD4 + 和CD8 + T细胞凋亡。研究还显示在每日两次3-4 mg/kg经口给药剂量的浓度下，其在体外可抑制犬T细胞增殖和细胞因子生成是强效和显著的，在常规治疗浓度下似乎不具有显著性。在人类研究中，在大多数T细胞淋巴增生性疾病（包括CETI）中已经描述了JAK/STAT信号转导的改变。这些改变包括功能获得性突变和无特定突变时的活化。细胞因子白细胞介素(IL)-15通过JAK1和JAK3传递信号，是肿瘤性T细胞的自分泌和旁分泌生长和活力因子，可能参与CETL的趋上皮性。卢可替尼是一种JAK1/2抑制剂，已被批准用于治疗人类骨髓增殖性肿瘤，一项正在进行的人类CETL患者临床试验的初步结果显示了积极的结果，在有JAK/STAT改变记录的患者中具有更大和更持久的反应。

In this case report, the treatment regimen resulted in rapid partial remission in a dog with CETL. Although we acknowledge that resolution of the secondary pyoderma would have contributed to the clinical improvement, we attribute the marked cytoreduction of neoplastic T lymphocytes to oclacitinib. The positive effect of oclacitinib may have been due to direct inhibition of T-cell proliferation, induction of T-cell apoptosis, anti-IL-15 effects or inhibition of upregulated JAK/STAT signalling. Although the duration of disease control was short (three months), this was comparable to other common treatment protocols and treatment with oclacitinib was well-tolerated with no adverse effects. Signs of the disease had been present for six months before presentation so it is possible that a better outcome could be seen in earlier cases. The dose used was high (0.7 mg/ kg twice daily) and it is unclear if a lower dose would have a similar effect. Twice daily dosing was chosen over once daily dosing owing to oclacitinib’s 4 h half-life.In conclusion, oclacitinib could be considered as a treatment option for canine CETL, as in this case its use resulted in marked histological cytoreduction of neoplastic cells, and in conjunction with treatment of the secondary pyoderma, marked and rapid clinical improvement. Furthermore it was very well-tolerated, with fewer potential adverse effects and less intense monitoring requirements than chemotherapy protocols. More studies are warranted to further evaluate its use.

在本病例报告中，治疗方案使CETL犬快速部分缓解。尽管我们承认继发性脓皮病的消退有助于改善临床，但我们将肿瘤性T淋巴细胞的显著减少归因于奥拉替尼。奥拉替尼的积极作用可能是直接抑制T细胞增殖、诱导T细胞凋亡、抗IL-15作用或抑制上调的JAK/STAT信号转导。尽管疾病控制的持续时间较短（3个月），但这与其他常见治疗方案相当，奥拉替尼治疗耐受良好，无不良反应。疾病体征在就诊前已存在6个月，因此在早期病例中可能观察到更好的结局。使用的剂量较高（0.7 mg/kg，每日两次），尚不清楚较低剂量是否会产生相似的作用。由于奥拉替尼的半衰期为4h，因此选择每日两次给药而不是每日一次给药。总之，可以认为奥拉替尼是犬CETL的一种治疗选择，因为在这种情况下，其使用导致肿瘤细胞的组织学显著减少，并且与继发性脓皮病的治疗联合使用时，临床改善显著且快速。此外，与化疗方案相比，其耐受性非常好，潜在不良反应更少，监测要求更低。需要更多的研究来进一步评价其使用。

Figure 3. Representative immunohistochemical staining results of biopsies from a Staffordshire bull terrier with cutaneous epitheliotropic T-cell lymphoma (CETL). Day 2 (a,b): The neoplastic lymphocytes are intermediate in size (averaging 1.5-fold greater diameter than an erythrocyte) and exhibit positive immunoreactivity for CD3, confirming a T-cell immunophenotype. Day 23 (c,d): Immunohistochemical findings for CD3 highlight the presence of low numbers of residual neoplastic T lymphocytes. Scale bars: (a, c) 100 µm; (b, d) 50 µm.

图3.皮肤趋上皮T细胞淋巴瘤(CETL)斯坦福牛头㹴活检的代表性免疫组织化学染色结果。第2天(a，b)：肿瘤性淋巴细胞大小居中（平均为红细胞直径的1.5倍），并显示CD3阳性免疫反应性，证实为T细胞免疫表型。第23天(c，d)：CD3的免疫组织化学结果突出显示存在少量残留肿瘤T淋巴细胞。比例尺：(a，c)100µm；(b，d)50µm。

Xwy

早看到这篇文章就好了 去年有只趋上皮型淋巴瘤的狗子 吃了泼尼松好一点 后来也安乐了，以后就可以用奥拉替尼了
感谢老师分享文献

龙医生