【兽医肿瘤前沿】交替使用雷巴福沙定（Tanovea）和多柔比星治疗 ...

胡璠

Alternating rabacfosadine and doxorubicin for treatment of naïve canine lymphoma 

交替使用雷巴福沙定和多柔比星治疗犬初治性淋巴瘤

 

翻译：徐晋   校对：胡璠

 

Abstract

摘要

The current standard of care treatment for canine lymphoma is a multi-agent, CHOP- based chemotherapy protocol. Single agent doxorubicin (DOX) is less burdensome; however, multi-agent chemotherapy protocols are often superior. The recently approved drug rabacfosadine (RAB, Tanovea) provides an attractive option for combination therapy with DOX, as both drugs demonstrate efficacy against lymphoma and possess different mechanisms of action. A previous study evaluating alternating RAB/DOX reported an overall response rate (ORR) of 84%, with a median progression-free survival time (PFS) of 194 days. The aim of this prospective trial was to evaluate the same protocol in an additional population of dogs. Fifty-nine dogs with treatment naïve lymphoma were enrolled. RAB (1.0 mg/kg IV) was alternated with DOX (30 mg/m 2 IV) every 21 days for up to six total treatments (3 cycles). Response assessment and adverse event (AE) evaluation were performed every 21 days using VCOG criteria. The ORR was 93% (79% CR, 14% PR). The median time to maximal response was 21.5 days; median PFS was 199 days. T cell immunophenotype and lack of treatment response were predictive of inferior outcomes. AEs were mostly gastrointestinal. Six dogs developed presumed or confirmed pulmonary fibrosis; four were grade 5. One dog experienced grade 3 extravasation injury with RAB that resolved with supportive treatment. These data mirror those of the previously reported RAB/DOX study, and support the finding that alternating RAB/DOX is a reasonable treatment option for canine lymphoma.

目前犬淋巴瘤的标准治疗是一种以CHOP为基础的多药化疗方案。单药多柔比星(DOX)负担较轻；然而，多药化疗方案往往更优。最近批准的药物雷巴福沙定 (rabacfosadine,RAB, Tanovea)为与多柔比星联合治疗提供了一个有吸引力的选择，因为两种药物对淋巴瘤均显示出疗效，且具有不同的作用机制。之前一项评估RAB/DOX交替治疗的研究报告，总缓解率(ORR)为84%，中位无进展生存期(PFS)为194天。这项前瞻性试验的目的是在另一群犬中评估相同的方案。59只治疗犬原始淋巴瘤纳入研究。RAB (1.0 mg/kg IV)与多柔比星(30 mg/m 2 IV)交替使用，每21天1次，共治疗6次(3个周期)。采用VCOG标准每21 天评估1次疗效和不良事件(AE)。ORR为93% (79% CR, 14% PR)。达到最大缓解的中位时间为21.5天；中位PFS为199 天。T细胞免疫表型和缺乏治疗反应是不良结局的预测因素。不良反应主要在胃肠道。6只犬发生了推测或确诊的肺纤维化；4个是5级。1只犬发生3级RAB外渗性损伤，经支持治疗后好转。这些数据反映了先前报道的RAB/DOX研究，并支持交替RAB/DOX是犬淋巴瘤的合理治疗选择。

 

KE YWOR DS canine, doxorubicin, lymphoma, rabacfosadine 

关键词：犬，多柔比星，淋巴瘤，雷巴福沙定

 

1 | INTRODUCTION

1 简介

The current standard of care treatment for canine lymphoma is a weekly to biweekly multi-agent, CHOP-based (cyclophosphamide-doxorubicin-vincristine-prednisone) chemotherapy protocol, with reported overall objective response rates (ORR) of 69%–100% and median progression free survival times (PFS) of 4.7-12.5 months. While this approach is feasible for some, others require an option with fewer and less frequent veterinary visits due to travel constraints or competing obligations. Single agent doxorubicin (DOX) is one treatment option that requires a reduced number of visits. However, outcomes reported utilizing single agent DOX appear inferior to multi-agent protocols, with ORRs of 59%–85% and median PFSs of 4.3-4.9 months. The recently FDA approved drug rabacfosadine (RAB, Tanovea) provides an additional single agent treatment option with reported ORRs of 87% and 74% and median PFSs of 4 and 3.5 months in studies in dogs with treatment-naive and relapsed lym- phoma, respectively.

目前犬淋巴瘤的标准治疗是每周一次至两周一次的多药chop(环磷酰胺-多柔比星-长春新碱-泼尼松)化疗方案，据报道总体客观缓解率(ORR)为69%-100%，中位无进展生存期(PFS)为4.7-12.5个月。虽然这种方法对一些国家是可行的，但由于旅行限制或相互竞争的义务，其他国家则需要一种越来越少的兽医就诊次数的选择。单药多柔比星(DOX)是一种需要减少就诊次数的治疗方案。然而，多柔比星单药治疗的结局似乎劣于多药治疗方案，ORR为59% ~ 85%，中位PFS为4.3 ~ 4.9个月。最近FDA批准的药物rabacfosadine (RAB, Tanovea)提供了一种额外的单药治疗选择，在对初治和复发性淋巴瘤犬进行的研究中，据报告ORR分别为87%和74%，中位PFS分别为4个月和3.5个月。

When considering the most efficacious treatment option for canine lymphoma, multi-agent chemotherapy protocols, like CHOP, are often preferred, as this approach potentially aids in the delay of multi-drug resistance. A protocol of alternating RAB and DOX offers an attractive option for a less time- and visit-intensive combina- tion chemotherapy protocol. In addition to having demonstrated effi- cacy against lymphoma as single agents, these drugs possess different mechanisms of action and different cumulative adverse effects. 2,7,8 A previous study evaluating alternating RAB/DOX administered at 3-week intervals reported an ORR of 84%, with a median PFS of 194 days. 9 While direct comparisons cannot be made, these data are within the range of outcomes reported with more complicated CHOP-based chemotherapy protocols. 4,5 The goal of this prospective, multi-centre trial was to confirm the results of the previous study evaluating alternating RAB/DOX in an independent population of dogs with treatment naïve multicentric lymphoma.

当考虑犬淋巴瘤最有效的治疗方案时，多药化疗方案，如CHOP，通常是首选，因为这种方法可能有助于延迟多药耐药。RAB和DOX交替化疗方案提供了一个有吸引力的选择，这是一种时间和就诊密集程度都更短的联合化疗方案。这些药物除了单药对淋巴瘤有效外，还具有不同的作用机制和不同的累积不良反应。之前一项评估RAB/DOX  3周交替给药的研究报告，ORR为84%，中位PFS为194日。虽然无法进行直接比较，但这些数据在较复杂的CHOP为基础的化疗方案报告的结局范围内。这项前瞻性、多中心试验的目的是评估在犬初治性多中心淋巴瘤群体中交替使用RAB和DOX的结果。

 

2 | METHODS

2 方法

2.1 | Inclusion/exclusion criteria

2.1 纳入和排除标准

Client-owned dogs weighing >5 kg, with previously untreated (includ- ing glucocorticoids, GC), cytologically or histologically confirmed, mul- ticentric, intermediate to large cell lymphoma were eligible for enrolment in this prospective, open-label phase 2 clinical trial evaluating alternating RAB and DOX. Confirmation of immunophenotype using immunohistochemistry, immunocytochemistry, flow cytometry or polymerase chain reaction (PCR) for antigen receptor rearrange- ment (PARR) was strongly recommended but not required. Similarly, post-mortem examination of dogs that died while on study was encouraged but not required.

这项前瞻性、开放标签的2期临床试验纳入了体重>5 kg、既往未接受过治疗(包括糖皮质激素)、细胞学或组织学证实的多中心、中至大细胞淋巴瘤病患。强烈推荐使用免疫组织化学、免疫细胞化学、流式细胞术或抗原受体重排(PARR)的聚合酶链反应(PCR)来确认免疫表型，但不是必需的。同样，鼓励对研究中死亡的犬进行尸检，但不是必需的。

 

Screening tests included physical examination, complete blood count (CBC), serum biochemical profile, and urinalysis. Thoracic radio- graphs were strongly recommended but not required for enrolment; baseline echocardiograms were not required. Dogs were required to have a modified VCOG performance score of either 0 or 1 on Day 0 10 with acceptable laboratory values defined as an absolute neutrophil count >2000 cells/μL, haematocrit >25%, platelet count >75 000/μL, serum creatinine <2.5 mg/dL, total bilirubin ≤ the upper normal limit, and transaminases ≤3 times the upper normal limit or, if >3 times the upper normal limit then serum bile acids needed to be within the normal reference interval. Dogs with known pulmonary fibrosis, a history of chronic pulmonary disease that could lead to fibrosis (e.g., chronic bronchitis), and West Highland white terriers were excluded. Dogs were not allowed to receive homeopathic or alternative therapies (excluding chondroitin sulphate, vitamins, essential fatty acids, and glucosamine) for their cancer while on the trial.

筛查包括体格检查、全血细胞计数(CBC)、血清生化指标和尿液分析。强烈推荐胸片检查，但不要求入组；不需要基础超声心动图。第0-10天改良VCOG评分为0或1分，中性粒细胞绝对值>2000个/μL，红细胞压积>25%，血小板计数>75 000个/μL，血肌酐<2.5 mg/dL，总胆红素≤正常上限，转氨酶≤正常上限3倍，如果>为正常上限3倍，则血清胆汁酸应在正常参考区间内。有已知肺纤维化、有可能导致纤维化的慢性肺部疾病病史(如慢性支气管炎)的犬和西高地白㹴被排除。在试验期间，犬的癌症不允许接受顺势疗法或替代疗法(不包括硫酸软骨素、维生素、必需脂肪酸和氨基葡萄糖)。

 

Each site's Institutional Animal Care and Use Committee and/or Clinical Review Board approved the study protocol, and signed informed owner consent was obtained prior to study entry. Other treatment options, including CHOP based therapies, were discussed with all owners, as enrolment in the study was optional.

各研究中心的机构动物护理和使用委员会和/或临床审查委员会批准了研究方案，并在进入研究前签署了知情同意书。与所有动物主人讨论了其他治疗方案(包括基于CHOP的治疗)，因为纳入研究是可选择的。

 

2.2 | Trial design

2.2 试验设计

The protocol entailed alternating RAB and DOX every 3 weeks for a planned six total treatments (i.e., three RAB/DOX cycles). Rabacfosa- dine was prescribed at 1.0 mg/kg and was reconstituted, diluted, and administered according to label instructions and as previously described. 2,3,9 Doxorubicin was obtained from commercial suppliers and prescribed at 30 mg/m 2 (25 mg/m 2 or 1 mg/kg for dogs ≤15 kg)  and reconstituted, ±diluted in 0.9% NaCl, and administered according each specific treatment site's chemotherapy administration protocol. Initially, concurrent treatment with GC was not allowed. However, at an early interim analysis, an unexpectedly high rate of suspected or confirmed pulmonary fibrosis (PF) was noted, and the protocol was amended to allow its use. The treatment schedule is outlined in Table 1. 

该方案要求每3周交替使用RAB和DOX，计划共治疗6个疗程(即3个RAB/DOX周期)。雷巴福沙定的处方剂量为1.0 mg/kg，并按照标签说明和之前的描述进行溶解、稀释和给药。多柔比星从商业供应商获得，处方剂量为30 mg/m 2(对于≤15 kg的犬，处方剂量为25 mg/m 2或1 mg/kg)，溶解后±稀释于0.9% NaCl中，并根据每个特定治疗部位的化疗给药方案给药。最初不允许同时使用GC治疗。然而，在早期期中分析时，我们注意到疑似或确诊肺纤维化(PF)的发生率出乎意料地高，因此对试验方案进行了修订，允许使用GC。治疗方案见表1。

Treatment response was based on calliper measurements of periph- eral lymph node target lesions using the Veterinary Cooperative Oncol- ogy Group (VCOG) Response Evaluation Criteria for Peripheral Nodal Lymphoma. 11 Dogs experiencing complete response (CR) received a total of three RAB/DOX cycles; thereafter, monthly rechecks were performed until progressive disease (PD) was noted. Dogs experiencing partial response (PR) or stable disease (SD) were allowed to continue treatment but were considered off study once they developed PD or completed the three RAB/DOX cycles. Once PD was noted, dogs were removed from the study and were eligible to pursue other treatment(s) as deemed appropriate by the attending oncologist and at the owner's discretion.

根据兽医肿瘤协作组(VCOG)外周淋巴结淋巴瘤疗效评价标准，以卡尺测量外周淋巴结靶病变作为治疗反应的依据。此后每月复查一次，直至出现疾病进展(PD)。出现部分缓解(PR)或疾病稳定(SD)的犬被允许继续治疗，但一旦它们发展为PD或完成三个RAB/DOX周期，则考虑退出研究。一旦发现PD，犬将被从研究中移除，并可接受主治肿瘤医师和主人酌情认为合适的其他治疗。

 

2.3 | Adverse event assessment

2.3 不良事件评估

Clinical, haematological, biochemical, and pulmonary AEs were assessed based on patient history provided by the owner, physical examination, blood work, and thoracic radiographs as outlined in Table 1. Adverse events were graded according to the Veterinary Cooperative Oncology Group Common Terminology Criteria for Adverse Events (VCOG-CTCAE) v1.1. 10 Dose-limiting toxicities (DLTs) were defined as any grade 3–5 non-hematologic toxicity, any uncom- plicated (e.g., no fever, bleeding, etc.) grade 4 hematologic toxicity, or any complicated grade 3–5 hematologic toxicity. Dermatological lesions deemed less than grade 3 according to VCOG-CTCAE v1.1 cri- teria but considered clinically significant and/or extensive enough to warrant protocol alteration were considered DLTs. Dose reductions and/or delays of up to 2 weeks were permissible to manage AEs. If a DLT was attributable to RAB or DOX, the dose of the offending drug was reduced by up to 20% for future administrations. Management of AEs was undertaken at the discretion of the attending clinician.

临床、血液学、生化和肺部AE根据主人提供的病史、体格检查、血液检查和胸片(如表1所示)进行评估。根据兽医肿瘤协作组不良事件通用术语标准(VCOG-CTCAE) 1.1对不良事件进行分级。剂量限制性毒性(DLT)定义为任何3-5级非血液学毒性、任何无并发症(如无发热、出血等)的4级血液学毒性或任何复杂的3-5级血液学毒性。根据VCOG-CTCAE v1.1标准，被认为小于3级的皮肤病变，但被认为有临床意义和/或广泛到需要改变方案的皮肤病变被视为DLT。药物减量和(或)延迟2周可用于治疗不良反应。如果DLT是由RAB或DOX引起，则在未来给药时，致病药物的剂量将降低至多20%。不良事件的处理由主治医师决定。

 

2.4 | Statistical analysis

2.4 统计分析

Continuous data were expressed as median and range, and categorical data as frequencies and percentages. The PFS was calculated from start of treatment to the date of PD or last follow-up for censored patients. Dogs were censored if they had not developed PD at the time of data analysis, or if they were withdrawn or lost to follow-up prior to developing PD. The Kaplan–Meier method was used to esti- mate PFS, and differences between groups were compared using log- rank analysis. Variables with values of p ≤ .05 were considered significant. All statistical analysis was performed with a commercial software package.

计量资料用中位数和范围表示，分类资料用频数和百分比表示。PFS从治疗开始至PD或病患的末次随访日期计算。如果犬在数据分析时未发展为PD，或者如果它们在发展为PD之前退出或失访，则将其删除。采用Kaplan-Meier法计算PFS, 对数秩检验法比较组间差异。p≤.05的变量被认为具有显著性。所有统计学分析均采用商业软件包进行。

 

 

Cell line validation statement: No cell lines were used in this study.

细胞系验证声明:本研究未使用细胞系。

 

 

3 | RESULTS

3 结果

Fifty-nine dogs were enrolled at participating sites including Univer- sity of Georgia, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, College of Veterinary Medicine, Veterinary Specialty Hospital of San Diego, VCA Animal Diagnostic Clinic, and Blue Pearl Seattle. The most common breeds included mixed breed dogs, Corgis, Labrador retrievers, and golden retrievers. Other patient characteristics including sex, age, body weight, concurrent GC use, and immunophenotype are summarized in Table 2. Glucocorticoids (prednisone at a dosage of 0.5–1.0 mg/kg/day for the duration of the protocol) were prescribed in 25 dogs. Only four dogs had abdominal imaging, so stage was not included in Table 2.

在包括乔治亚大学兽医学院、伊利诺伊大学香槟分校兽医学院、圣地亚哥兽医专科医院、VCA动物诊断诊所和西雅图蓝珍珠在内的参与中心的59只犬被纳入研究。最常见的品种包括混血犬、柯基犬、拉布拉多寻回犬和金毛寻回犬。表2总结了病患的其他特征，包括性别、年龄、体重、是否同时使用GC和免疫表型。我们给25只犬开了糖皮质激素(在试验期间，泼尼松剂量为每天0.5-1.0 mg/kg)。只有4只犬进行了腹部影像学检查，因此表2中未包括分期。

 

In the 56 dogs evaluable for response assessment, the overall response rate (ORR, CR + PR) was 93% (n = 52). Best responses were CR in 79% (n = 44), PR in 14% (n = 8), and SD in 7% (n = 4; Figure 1). The median time to maximal response was 21.5 days (range: 6-89 days). Three dogs were withdrawn prior to the first response assessment, and therefore not included in ORR calculations. Reasons for withdrawal from the trial included presumed progressive disease (n = 1), owner concerns about AEs (n = 1), and euthanasia after a bite incident (n = 1).

可评价疗效的56只犬中，总有效率(ORR, CR + PR)为93% (n = 52)。最佳反应为79% (n = 44)完全缓解，14% (n = 8)部分缓解，7% (n = 4;达到最大缓解的中位时间为21.5天(范围:6-89天)。3只犬在第一次反应评估前被移除，因此不包括在ORR计算中。退出试验的原因包括推测疾病进展(n = 1)，主人担心不良事件(n = 1)，以及咬伤后实施安乐死(n = 1)。

 

The overall median PFS was 199 days (range: 19 days to not reached). Twelve dogs were censored from PFS analysis. One dog remained on study in CR at the time of manuscript preparation (1227 days follow-up), 6 were withdrawn due to owner request or non-compliance, 3 were withdrawn due to the attending clinician's concerns about AEs (2 were progressive ALT elevations; 1 was derma- topathy), and 2 were withdrawn for other reasons including lack of a CR by the end of the protocol and owner-requested euthanasia. The median follow-up time for all censored patients was 66.5 days (range: 7-1227 days).

中位PFS为199 天(范围:19 天至未达到)。12只犬在PFS分析中被剔除。在论文撰写时(1227天的随访)，1只犬仍处于CR，6只犬因主人的要求或不依从而退出研究，3只犬因主治医师担心不良事件而退出研究(2只为ALT进行性升高；1只为皮肤病变)，2只因其他原因退出试验，包括在试验方案结束时未到CR和主人要求的安乐死。所有病患的中位随访时间为66.5天 (7-1227天)。

 

On univariate analysis, T cell immunophenotype and lack of treat- ment response were predictive of inferior outcomes. The median PFS for B cell versus T cell lymphoma was 199 and 61.5 days, respectively (p < .0001; Figure 2). The median PFS for dogs experiencing CR as their best response (217 days) was significantly longer than PFSs for dogs with PR (91 days) or no response (36 days) (Bonferroni-adjusted p = .01 and .026, respectively; Figure 3).

在单因素分析中，T细胞免疫表型和治疗反应差是不良预后的预测因素。B细胞淋巴瘤和T细胞淋巴瘤的中位PFS分别为199天和61.5天(p < 0.0001；最佳反应为CR的犬的中位PFS(217天)显著长于PR(91天)或无反应的犬的PFS (36天)(bonferroni校正p值分别为.01和.026;图3)。

 

Fifty-five dogs were evaluable for AE assessment; of these, 36 completed the planned 3 RAB/DOX cycles. All AEs are outlined in Table S1. In summary, gastrointestinal and hematologic AEs were most common for both drugs. Dose-limiting GI AEs occurred after RAB in 4 dogs and after DOX in 7 dogs. Depending on clinician pref- erence, these were managed with maropitant, ondansetron, metroni- dazole, tylosin, and/or mirtazapine. Dose-limiting hematologic AEs occurred after RAB in no dogs and after DOX in 6. Weight loss specifically was assessed over the duration of the protocol, with 5 dogs experiencing grade 3 or 4 weight loss. There were 3 RAB dose reductions (to 0.82 mg/kg) and 10 DOX dose reductions (10%–20%) instituted to manage AEs.

55只犬可用于AE评估；其中36只完成了计划的3个RAB/DOX周期。表S1列出了所有AE。总之，胃肠道和血液学不良反应是两种药物最常见的不良反应。RAB后4只犬发生剂量限制性胃肠道AE， DOX后7只犬发生剂量限制性胃肠道AE。根据临床医师的偏好，这些病患使用马罗匹坦、昂丹司琼、甲硝唑、泰乐菌素和/或米氮平进行治疗。在RAB后没有犬发生剂量限制性血液学不良反应，在DOX后有6只犬发生。在研究过程中，我们对体重减轻进行了具体评估，其中5只犬经历了3级或4级体重减轻。RAB减量3次(减量至0.82 mg/kg)， DOX减量10次(减量10%-20%)以控制不良反应。

 

Specific to RAB, dermatopathy occurred in 8 dogs (grade 1 in 4; grade 2 in 4) with signs including alopecia, erythema, scaling, hyper- pigmentation, and discomfort. Grade 1 otitis externa occurred in 3 dogs. Depending on clinician preference, AEs were managed with RAB dose reduction and/or delay, topical or systemic GCs, and cefpodoxime. One dog was withdrawn from the study because of dermatologic AEs which persisted after RAB dose reduction.

8只犬出现RAB特异性皮肤病变(4只为1级；4级为2级)，症状包括脱毛、红斑、皮屑、色素沉着和不适。3只犬发生1级外耳炎。根据临床医师的偏好，AE的处理包括RAB减量和(或)延迟给药、局部或全身GC以及头孢泊肟。1只犬因RAB减量后仍出现皮肤不良反应而退出研究。

 

Six dogs developed confirmed (n = 2) or presumed (n = 4) pulmonary fibrosis (PF). The median age of dogs at the time of development of PF was 5.5 years (range: 4-10). There were 3 spayed females, 2 castrated males, and 1 intact male. Interestingly, 2 of the 6 were Corgis. Clinical signs were present in 5, and included cough, dyspnea, tachypnea, and exercise intolerance. The median time from the start of the protocol to development of respiratory clinical signs was 120 days (range: 96–280 days). The median time from development of clinical signs until death was 5.5 days (range: 0–152 days). Only one of these dogs was receiving a GC (prednisone) while on RAB/DOX, and all 6 had received the 3 planned cycles of RAB/DOX when the respiratory clinical signs began. Only one had clear evidence of lymphoma recrudescence externally (enlarged lymph nodes) when PF was noted.

6只犬发展为确诊(n = 2)或推测(n = 4)的肺纤维化(PF)。犬发生PF的中位年龄为5.5岁(范围：4 ~ 10岁)。3例为绝育雌性，2例为去势雄性，1例为未去势雄性。有趣的是，6只中有2只是柯基犬。5例有临床症状，包括咳嗽、呼吸困难、呼吸急促和运动不耐受。从方案开始到出现呼吸系统临床症状的中位时间为120 d(范围：96-280 d)。从出现临床症状至死亡的中位时间为5.5 d(范围：0 -152 d)。这些犬中只有1只在RAB/DOX治疗期间接受了GC(泼尼松)，所有6只在呼吸系统临床症状开始时已经接受了计划的3个周期的RAB/DOX治疗。发现PF时，仅1例有明确的外部复发证据(淋巴结肿大)。

 

Five of the dogs with PF had thoracic radiographs performed at baseline. Of these, 3 had a diffuse interstitial pattern, thought to be consistent with pulmonary lymphoma, and 2 were deemed‘radio- graphically normal’.  Five of the 6 dogs had thoracic radiographs per- formed at the onset of respiratory clinical signs. A patchy to diffuse interstitial to alveolar pattern was reported in all 5 dogs. In addition, one dog had a pneumothorax, and one dog had a pneumomediasti- num. None of the dogs were deemed radiographically ‘normal’.

5只有PF的犬在初诊时进行了胸片检查。其中3例为弥散性间质型，被认为与肺淋巴瘤一致，2例被认为“放射学正常”。6只犬中有5只在出现呼吸系统临床症状时进行了胸片检查。5只犬均呈斑片状至弥散性肺泡间质样改变。另外，有一只犬出现了气胸，还有一只犬出现了纵隔积气。所有这些犬的X线表现都不正常。

 

Four dogs died or were euthanized as a result of respiratory clinical signs. Attempted treatments included GCs (prednisone or dexamethasone SP), antibiotics, L -asparaginase ± lomustine, oxygen (n = 2), albuterol, clopidogrel, butorphanol, and diphenhydramine, none of which was effective. Two of the four dogs had histopatho- logic examination of the lungs. One had a complete necropsy, where PF was confirmed histologically, and no evidence of lym- phoma was observed. The other dog had histopathology of the lungs only. Moderate to marked diffuse, subacute fibrinous pneu- monia and bronchiolitis were reported with no evidence of fibrosis. However, the pathologist commented that the changes were acute and could have eventually led to fibrosis.

4只犬因呼吸系统症状死亡或安乐死。尝试的治疗包括糖皮质激素(泼尼松或地塞米松SP)、抗生素、L -门冬酰胺酶±洛莫司汀、氧气(n = 2)、沙丁胺醇、氯吡格雷、布托啡诺和苯海拉明，均无效。4只犬中有2只进行了肺组织病理学检查。1例进行了完整的尸检，病理证实为PF，未观察到淋巴瘤的证据。另一只只做肺组织病理学检查。报告中度至显著的弥漫性亚急性纤维素性肺炎和毛细支气管炎，无纤维化证据。然而，病理学家评论说，这些变化是急性的，可能最终导致纤维化。

 

Two dogs lived with PF. Both were treated with GC (prednisone) from the onset of the respiratory signs, and both were later eutha- nized because of progressive lymphoma, 55 and 160 days after the presumed diagnosis of PF. One had a necropsy performed, and PF was confirmed on histopathology with no evidence of lymphoma seen in the lung sections.

2只犬伴着PF生存。从出现呼吸系统症状开始，2只犬都接受了泼尼松治疗，在推测为PF的55天和160天后，2只犬都因进展性淋巴瘤而被安乐死。1只犬进行了尸检，通过组织病理学证实了PF，但在肺切片中没有淋巴瘤的证据。

 

One dog experienced grade 3 extravasation injury with RAB. A clean-stick catheter was placed in the left lateral saphenous vein with- out complication; however, during the infusion, perivascular swelling was noted. The infusion was discontinued. There was an attempt to remove any residual perivascular RAB, and a cold compress was applied. The remainder of the RAB dose was administered success- fully via a different vein (right lateral saphenous). Approximately 7 days after the event, a 6.5 ? 4.5 cm area of swelling and erythema with purulent discharge was noted over the left lateral saphenous vein. Cephalexin was prescribed, and the area appeared completely healed approximately 2 months after the extravasation event.

1只犬发生3级RAB外渗性损伤。左外隐静脉置入清洁导管，无并发症发生；然而，在输注过程中，观察到血管周围肿胀。停止输注。尝试清除血管周围残留的RAB，并进行冷敷。剩余的RAB剂量成功给药——完全通过另一条静脉(右侧大隐静脉)。事件发生约7日后，在左外侧隐静脉上方观察到一个面积约 6.5 ×4.5 cm的肿胀和红斑伴脓性渗出物的区域。给病患开了头孢氨苄，约2个月后，伤口完全愈合。

 

4 | DISCUSSION

4 讨论

 

The results of this study provide evidence that alternating RAB/DOX ± prednisone is an effective treatment for dogs with treatment-naïve, multicentric, intermediate to large cell lymphoma, with a 93% ORR and a median PFS of 199 days. These results mirror those of the previously reported RAB/DOX study VC-006 9 (Figure 4) and are comparable to those reported for CHOP based protocols. It is extremely rare in veterinary medicine that a confir- matory prospective study of a novel therapy is performed after the results of an initial prospective study are published. The fact that the results are so remarkably similar to the previous results sup- ports the original contention that this protocol results in outcomes that are very similar to the current standard of care with a markedly reduced number of required visits.

本研究的结果证明RAB/DOX±泼尼松交替治疗初治性多中心中至大细胞性淋巴瘤是一种有效的治疗方法，ORR为93%，中位PFS为199天。这些结果与之前报告的RAB/DOX研究VC-006 9的结果一致(图4)，并且与基于CHOP方案的研究结果相似。在兽医学中，在最初的前瞻性研究结果发表后再对一种新疗法进行确证性前瞻性研究是极为罕见的。本研究的结果与之前的结果非常相似，这一事实支持了最初的观点，即本研究方案产生的结局与目前的标准治疗非常相似，并且所需的就诊次数显著减少。

 

Adverse events were similar to those previously reported and included GI effects, dermatopathy and PF. 3,9,12-14 One dog experienced grade 3 extravasation injury. RAB is known to be a vesicant, but this is the first report of the management and outcome of this AE with RAB. Most, but not all AEs were self-limiting and resolved with supportive care and/or dosage modification.

不良事件与之前报道的相似，包括胃肠道反应、皮肤病变和PF 。1只犬发生了3级外渗性损伤。RAB是已知的起疱剂，但这是第一份关于RAB治疗AE和结局的报告。大多数(但不是所有)不良事件是自限性的，并在支持性治疗和/或调整剂量后缓解。

 

Pulmonary fibrosis is a known AE of RAB, reportedly occurring in ?4% of treated dogs. Of notable concern in this population was that 10% of dogs (n = 6) developed non-specific respiratory clinical signs including cough, dyspnea, tachypnea, and exercise intolerance. In order to avoid underestimating the incidence, PF was presumed (but not confirmed) in 4 dogs and confirmed with histopathology only in 2. The cause of RAB-associated PF is unknown. It is unknown if concurrent treatment with glucocorticoids reduces the risk of PF, but only one of these dogs received prednisone while on the RAB/DOX protocol. It is also unknown when PF develops after treatment with RAB, and if the risk increases as the cumulative drug dosage increases. All of these dogs had received the 3 planned cycles of RAB/DOX, and the median time from the start of the protocol to development of respiratory clinical signs was 120 days (range: 96–280 days).

肺纤维化是RAB的一种已知AE，据报道在接受治疗的犬中发生约4%。值得关注的是，10%的犬(n = 6)出现了非特异性呼吸系统临床症状，包括咳嗽、呼吸困难、呼吸急促和运动不耐受。为了避免低估发病率，我们推测(但未证实)4只犬发生了PF，只有2只经组织病理学证实。RAB相关PF的病因尚不清楚。目前尚不清楚同时使用糖皮质激素治疗是否可以降低PF的风险，但在RAB/DOX方案中，只有1只犬接受了泼尼松治疗。也不清楚RAB治疗后何时发生PF，以及是否随着累积药物剂量的增加而风险增加。所有犬均接受了3个RAB/DOX治疗周期，从开始治疗到出现呼吸系统临床症状的中位时间为120 d(范围：96-280 d)。

 

Because RAB is a relatively new drug, the features of RAB- associated PF are poorly understood. This is complicated by the fact that few dogs have histopathological examinations of their lungs even when PF is suspected. There does not appear to be a pathognomonic histologic pattern of RAB-associated PF. In fact, in the authors' experi- ence, some pathologists appear to include RAB-associated PF when any lung pathology is seen in a patient with a history of treatment with RAB. Further investigation is needed to better understand this AE.

由于RAB是一种相对较新的药物，因此对RAB相关PF的特征知之甚少。这是复杂的事实，很少有犬的肺组织病理学检查，即使是在怀疑PF。RAB相关性PF似乎没有一个病理诊断的组织学模式。事实上，根据作者的经验，当在有RAB治疗史的病患中看到任何肺部病理时，一些病理学家似乎将RAB相关性PF包括进来。需要进一步的研究来更好地理解这种AE。

 

In humans, drug-induced interstitial lung disease (DIILD) occurs when drug exposure causes inflammation and oedema of lung; in some cases, this eventually leads to lung fibrosis. 15,16 Anti-neoplastic drugs including but not limited to bleomycin, gemcitabine, epidermal growth factor receptor (EGFR)-targeted therapies, mechanistic target of rapa- mycin (MTOR) inhibitors, and immune checkpoint inhibitors appear to be the leading culprits. Risk factors for the development of DIILD can vary but can include increased age and pre-existing lung disease. 15–17 A variety of treatments are used for PF secondary to DIILD, commonly including discontinuation of the offending drug and GCs.

在人类，当药物暴露导致肺部炎症和水肿时，就会发生药物性间质性肺疾病(DIILD)。在某些情况下，这最终会导致肺纤维化。包括但不限于博来霉素、吉西他滨、表皮生长因子受体(EGFR)靶向治疗、雷帕霉素机制靶点(MTOR)抑制剂和免疫检查点抑制剂在内的抗肿瘤药物似乎是主要的罪魁祸首。发生DIILD的危险因素可能各不相同，但可能包括年龄增加和原有肺部疾病。DIILD继发PF有多种治疗方法，通常包括停用致病药物和GC。

 

Predictors of inferior outcomes in this study included T cell immu- nophenotype and lack of a treatment response. These have proven to be significant factors in predicting outcome in historical RAB clinical trials and are unlikely to be specific to RAB. Peripheral large cell T cell lymphoma has historically been a more difficult disease to treat, carrying a poorer prognosis in several studies. While some may argue that alkylator-rich protocols 20-22 (as compared to CHOP-based protocols) are superior in the treatment of peripheral large cell T cell lymphoma, this has not been proven in any prospective clinical trials.

在本研究中，预后不良的预测因素包括T细胞免疫表型和缺乏治疗反应。在历史的RAB临床试验中，这些已被证明是预测结局的重要因素，并且不太可能是RAB的特异性因素。外周大细胞T细胞淋巴瘤历来是一种较难治疗的疾病，多项研究表明其预后较差。虽然一些人可能认为富含烷化剂的方案(与基于CHOP的方案相比)在外周大细胞T细胞淋巴瘤的治疗中更优，但这一观点尚未在任何前瞻性临床试验中得到证实。

 

Limitations of this study include the lack of required thoracic radiographs prior to and during treatment. However, baseline thoracic radiographs were performed in 5 out of the 6 that developed suspected PF, and none of the other dogs were reported to develop any respiratory signs. Perhaps a more important limitation is that necropsies were not required, so it is possible that we have over- estimated the percentage of dogs developing PF in this population. Finally, it can be argued that the treatment protocol was not the same for all dogs, as prednisone was allowed in some. At interim analysis, we could not ignore the fact that 5 dogs had developed presumed RAB-associated PF. In attempt to mitigate the frequency of this AE, we opted to allow the use of prednisone for the duration of the protocol.

本研究的局限性包括在治疗前和治疗期间未进行必要的胸片检查。然而，在6只出现疑似PF的犬中，有5只进行了初诊时的胸片检查，其他犬均未报告出现任何呼吸道症状。也许一个更重要的局限性是未推荐尸检，所以我们可能高估了在这个种群中发展为PF的犬的百分比。最后，可以提出的是，并非所有犬的治疗方案都是相同的，因为某些犬可以使用泼尼松。在中期分析中，我们不能忽视5只犬发生了推测的RAB相关PF的事实。为了减少这种AE的发生频率，我们选择在试验期间使用泼尼松。

In conclusion, RAB/DOX is an effective treatment for treatment naïve canine lymphoma. A clear advantage of this protocol over CHOP is the need for fewer and less frequent veterinary visits. While presumably low, the risk of fatal PF should not be discounted.

综上所述，RAB/DOX是一种有效的治疗初治性犬淋巴瘤的方法。与CHOP方案相比，该方案的一个明显优势是需要的就诊兽医的次数越来越少。虽然可能较低，但不应忽视致死性PF的风险。

 

 

 

第  天	雷巴福沙定	多柔比星	PE	淋巴结评估	全血细胞计数	血清生化	尿液分析	胸片
参加试验前(第-7至第-1天)			X		X	X	X	X
0	X		X	X	X a	X a	X a
7			X		X
21		X	X	X	X
28			X		X
42	X		X	X	X	X	X
63		X	X	X	X
84	X		X	X	X	X	X	X
105		X	X	X	X			X
月度复查			X	X				隔月一次

a If CBC, serum chemistry, and urinalysis were performed and evaluated within 7 days of Day 0, these were not repeated on Day 0.

a如果在第0日之后的7日内进行了CBC、血清化学和尿液分析，则在第0日不再重复这些检查。

TABLE 1 Study schedule.

表1研究时间表

 

 

 

		犬只数
年龄	8岁（2-15岁）
体重（kg）	26.2 kg（4.7–48 kg）
性别	雄性去势	35
	雄性未去势	4
	雌性绝育	20
免疫表型	B细胞	47
	T细胞	5
	CD3+ CD79a+	1
	B 细胞± TZL	1
	未做	5
泼尼松	是a	25
	否	34

a Prednisone was prescribed at a dosage of 0.5–1.0 mg/kg/day for the duration of the protocol.

在研究方案期间，我们开出了每日0.5-1.0 mg/kg剂量的泼尼松。

TABLE 2 Baseline characteristics of patient population (n = 59).

表2病患群体的基线特征(n = 59)

 

 

FIGURE 1 Number of responders based on each dog's best response (n = 56); CR = 44% or 79%, PR = 8% or 14%, SD = 4% or 7%. Three dogs were not evaluated (NE).

图1根据每只犬的最佳反应得出的反应犬只数(n = 56);CR = 44%或79%，PR = 8%或14%，SD = 4%或7%。3只犬未评价(NE)。

 

FIGURE 2 PFS in days based on immunophenotype; B cell = 199 days versus T cell = 61.5 days.

图2基于免疫表型的PFS天数;B细胞= 199天，T细胞= 61.5天。

 

FIGURE 3 PFS in days based on patient's best response; CR = 199 days, PR = 61.5 days; NR = 36 days.

图3基于病患最佳应答的PFS;CR = 199天, PR = 61.5天;NR = 36天。

 

FIGURE 4 PFS in days for VC-006, Thamm et al. 4 (194 days) as compared to the present study VC-016 (199 days).

图4与本研究VC-016(199天)相比，Thamm等人VC-006的PFS天数(194天)。

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