Lymphoma is the most common malignancy in cats, and since the development of programs to control feline leukemia virus infection, the cat’s alimentary tract is the site where lymphomas most frequently occur. Small cell lymphomas (SCLs), which are composed of small, well-differentiated lymphocytes and are classified histologically as low grade, generally have a better response to treatment and longer survival time compared with large cell lymphomas. In this retrospective study, data was gathered regarding treatment-associated toxicity, response to rescue chemotherapy, and treatment outcome of cats diagnosed with SCL of the alimentary tract and other anatomic locations. Based on previous studies, prevalence rates of low grade lymphomas may be as high as 37-75% of all feline lymphomas. There is very little in the literature regarding potential to discontinue chemotherapy, effectiveness of rescue chemotherapy, or treatment outcome with extra-intestinal disease.
In the cases reviewed, confirmation of diagnosis of SCL was determined by histopathology, except in 3 cases where cytology in conjunction with flow cytometry or polymerase chain reaction for antigen receptor rearrangement (PARR) was utilized. The study group was composed of 34 males and 22 females, all gonadectomized. Breeds represented were domestic shorthair (n=47), domestic longhair and mediumhair (n=5), 2 Maine coons, and one Siamese and one Ocicat. The median age of the patients was 12.3 years (range, 3.8-16.5 years). In 37 patients the SCL was confined to the alimentary tract only, and in 12 additional patients it involved other sites as well as the gastrointestinal tract. Four of the patients had SCL in the liver only. One patient had SCL in the spleen only, several in lymph nodes only, and another, in a paw of the thoracic limb. Vomiting (n=27), weight loss (n=24), and anorexia (n=22) were the most common initial presenting complaints, followed by diarrhea, lethargy, elevated liver enzymes, increased appetite, enlarged lymph nodes, and abdominal mass, as well as several other clinical signs. The most common laboratory abnormalities included a mature neutrophilia (19.4% of patients) and anemia (12.9%), various elevated liver enzymes, elevated BUN (18.9%), and creatinine (13.2%). Serum total T4 concentrations were normal in 28 of 35 patients tested (80%). No patients tested positive for either the feline leukemia virus or the feline immunodeficiency virus.
All cats received a glucocorticoid and chlorambucil as a first line chemotherapy protocol. The treatment protocol was discontinued at one year after the start of chemotherapy if restaging diagnostics (resolution of clinical signs, abnormal physical examination findings, and abnormal ultrasound results) indicated a complete clinical response. Those cats who did not have a complete clinical response at one year restaging continued on chemotherapy. Dosing information was available for most of the patients; 28/37 received prednisolone or prednisone at a dose of 5 mg PO q 24 hours; 21/37 patients with available dosing information received chlorambucil at a dose of 2 mg PO every other day. In the remaining patients for whom dosing information was available, other glucocorticoid/chlorambucil dosing regimens were used.
Nineteen of the patients (33.9%) experienced adverse events associated with chemotherapy; toxicity of chemotherapy was considered uncommon and generally mild. Of the 25 documented adverse events, low-grade myelosuppression (n=11) was the most common, followed by a few adverse events associated with the gastrointestinal tract (n=7), also generally mild, and liver (n=7). Cases involving hepatotoxicity were more severe; in patients experiencing hepatotoxicity, discontinuation of the chlorambucil reversed the hepatotoxicity. Over half of the adverse events required treatment delays; an additional 32% required discontinuation of prednisolone or prednisone and chlorambucil and initiation of a different chemotherapy protocol for treatment. The rest of the patients who experienced toxicity required either a dosage reduction, supportive care only, or no treatment to resolve their adverse event(s).
After 30 days of initiating glucocorticoid/chlorambucil treatment, 82% of the cats (n=46) either had partial clinical response (57.8%) or complete clinical response (22.8%). By 90 days, 48 (85.7%) of the cats had responded to chemotherapy (50.8% complete clinical response, 35.0% partial clinical response). Although 23 (41.1%) of the cats developed progressive disease during the follow-up period, the median progression-free survival was 1078 days (range 2-2479) days. The location of the SCL, whether gastrointestinal or extraintestinal, was not associated with progression-free survival time. In 22 of the patients in which the disease was found to have progressed, one or more rescue protocols was implemented, usually reintroduction of the prednisone and chlorambucil, and in a few patients, either COP (cyclophosphamide, vincristine, prednisone), prednisone and lomustine, or prednisone and cyclophosphamide. The overall response rate for the first attempt at rescue chemotherapy was 59%, with 45% achieving complete clinical response and 14% demonstrating partial clinical response. Cats receiving reintroduced prednisone and chlorambucil had a significantly longer progression-free survival (850 days) than those receiving rescue prednisone/lomustine (332 days).
The overall survival time for all cats with SCL was 1317 days. For those cats with SCL confined to the alimentary tract only, the median survival time was 1148 days (range 15-2479), while those with SCL in extraintestinal locations had a median survival time of 1375 days (range 208-1805). Of the 19 cats who died, 10 died due to tumor-related causes, and 9 died from non-tumor related causes. There is a favorable prognosis for cats with SCL who are treated with the glucocorticoid/chlorambucil protocol, regardless of whether the disease is confined to the alimentary tract or is extraintestinal. Progression-free and overall survival times for patients evaluated in this study are either consistent with or even longer than those reported in previous studies. A new and hopeful finding reported in the present study is that the original glucocorticoid/chlorambucil protocol may be discontinued at a defined time period following documentation of complete clinical response. Rather than continuing this treatment on a lifelong basis after initial diagnosis, regardless of subsequent attainment of complete clinical response, this same protocol may be re-initiated later as a probably successful first-line rescue therapy in patients that go out of remission.
A prospective study of cats diagnosed with SCL in which a consistent glucocorticoid/chlorambucil dosing protocol is utilized in all patients would potentially provide more information regarding progression-free interval and survival time, as well as response to rescue therapy. As the metabolism of the prodrug prednisone to prednisolone is considered to be inefficient in cats, and studies have shown that plasma concentrations of prednisolone are 4 to 5 times higher when this drug is given orally to cats rather than prednisone, such a study could also compare the response of patients with SCL to a prednisolone/chlorambucil protocol versus a prednisone/chlorambucil protocol. [PJS]