Prognostic factors for treated canine malignant lymphoma.

The aim of this study was to investigate the prognostic importance of different clinical, immunohistologic and tumor proliferation characteristics in dogs with malignant lymphoma treated with chemotherapy. From 74 dogs with malignant lymphoma at least one enlarged peripheral lymph node was taken for biopsy before chemotherapy following a standardized protocol (vincristine, cyclophosphamide, prednisolone, doxorubicin, and L-asparaginase). The variables evaluated as prognostic factors were age, sex, and tumor stage, as well as histomorphologic grade (Kiel classification, Working Formulation), immunophenotype (using markers for CD3 and CD79a), and cell proliferation (Ki-67, proliferation cell nuclear antigen, mitotic index, and argyrophil nucleolar organizer regions [AgNORs]) in extirpated lymph nodes. All markers were used on routinely formalin-fixed, paraffin-embedded tissues. The AgNORs were assessed qualitatively, based on the AgNOR pattern distribution, and quantitatively using image analysis and routine counting. In both univariate and multivariate survival analyses, AgNORs were a valuable prognostic marker for the treatment of canine malignant lymphomas. Based on the results of the multivariate analysis longer survival time correlated with a B-cell type, a larger mean AgNOR area, a larger total AgNOR area, a shorter distance between two AgNORs, and a smaller AgNOR area to nucleus ratio. Longer disease-free survival time correlated with a smaller number of AgNORs per nucleus, a larger mean AgNOR area, a larger maximal AgNOR area, and a larger total AgNOR area. This study clearly demonstrates the additional benefit of the use of AgNORs in predicting treatment outcome in dogs with malignant lymphoma.     

A case of T-cell chronic lymphocytic leukemia progressing to Richter syndrome with central nervous system involvement in a dog

An 8-year-old neutered Beagle dog was presented with polyuria and polydipsia. Routine clinicopathologic testing showed a significant lymphocytosis and proteinuria. Lymphocytes were of small to intermediate in size with a mature morphology. Infectious disease screening was negative. PCR for antigen receptor gene rearrangements showed a clonal T-cell receptor (TCR) rearrangement consistent with T-cell chronic lymphocytic leukemia (CLL). Bone marrow cytology showed <30% lymphocytes, while the proportion in splenic fine-needle aspirate cytology was considered increased. The dog was initially monitored but started on prednisolone and chlorambucil therapy 2 months later due to worsening clinical signs and progressive lymphocytosis. After an additional 2 weeks, the dog developed multifocal spinal pain and single-node lymphadenomegaly. Cytology of the lymph node showed a monomorphic population of large lymphoblasts consistent with lymphoma. Cytology of a cerebrospinal fluid sample also showed large lymphoblasts. PCR for antigen receptor gene rearrangement at both sites showed a clonal TCR rearrangement of the same molecular size as in the initial leukemic cells. The dog was diagnosed with a transformation of the CLL to Richter syndrome (RS) with involvement of the central nervous system (CNS). Therapy was started with L-asparaginase and an increased dose of prednisolone; however, the dog was euthanized due to progressive clinical signs. To our knowledge, this is the first report of canine RS with direct involvement of the CNS.     

Treatment of dogs with lymphoma using a 12-week, maintenance-free combination chemotherapy protocol

BACKGROUND: Treatment of lymphoma in dogs by long-term chemotherapy has favorable results. However, the efficacy of short-term, maintenance-free treatment protocols on remission and survival times in dogs has not been determined. HYPOTHESIS: That treatment using a 12-week chemotherapy protocol would be associated with satisfactory treatment outcome in dogs with lymphoma. ANIMALS: 77 dogs with histologically or cytologically confirmed diagnosis of lymphoma. METHODS: Prospective clinical trial in which dogs were treated with a 12-week chemotherapy protocol consisting of L-asparaginase, vincristine, cyclophosphamide, doxorubicin, and prednisolone. RESULTS: Complete remission rate was 76.3%. Multivariate logistic regression analysis revealed that clinical substage (P = .006) and immunophenotype (P = .003) had a significant influence on the likelihood of a dog achieving complete remission. Median duration of first complete remission was 243 days (range 19-1,191 days). The 6-month, 1-year, and 2-year remission rates were 68%, 28%, and 16%, respectively. In the multivariate analysis of patient variables, immunophenotype (P = .022) revealed a significant influence on first remission duration. Toxicosis was mild with the exception of 1 treatment-associated death. CONCLUSIONS AND CLINICAL IMPORTANCE: In this group of dogs the 12-week maintenance-free chemotherapy protocol was well tolerated and had satisfactory results.     

Chemotherapy of lymphoma in 75 cats

Seventy-five cats with lymphoma were treated with combination sequential chemotherapy consisting of vincristine, cyclophosphamide, and methotrexate. Thirty-nine cats had mediastinal, 16 had multicentric, 14 had alimentary, and 6 had renal lymphoma. The median survival time of the 75 cats was 8 weeks, with a mean of 32 weeks. Sixty-two cats had follow-up evaluation until death or cure and had a median survival time of 7 weeks, with a mean of 37 weeks. Of the 62 cats, 32 (52%) attained complete remission, with a median remission duration of 16 weeks and a mean of 46 weeks. The addition of prednisolone and/or L-asparaginase to the protocol did not improve the results. Sixteen cats with multicentric lymphoma had the longest survival times (median, 18 months) and remission durations (median, 25 months). Prognostic factors were evaluated in each anatomic form of lymphoma.     

Efficacy of a continuous, multiagent chemotherapeutic protocol versus a short-term single-agent protocol in dogs with lymphoma

OBJECTIVE: To compare response rates and remission and survival times in dogs with lymphoma treated with a continuous, multiagent, doxorubicin-based chemotherapeutic protocol or with a short-term single-agent protocol incorporating doxorubicin. DESIGN: Nonrandomized controlled clinical trial. ANIMALS: 114 dogs with lymphoma. PROCEDURES: Dogs were treated with a chemotherapeutic protocol consisting of L-asparaginase, vincristine, cyclophosphamide, doxorubicin, methotrexate, and prednisolone (n=87) or doxorubicin alone (27). RESULTS: 63 of 86 (73%) dogs treated with the multiagent protocol (data on response was unavailable for 1 dog) and 14 of 27 (52%) dogs treated with the single-agent protocol had a complete remission. Dogs with lymphoma classified as substage相似文献   

Combination chemotherapy with L-asparaginase, lomustine, and prednisone for relapsed or refractory canine lymphoma

BACKGROUND: Canine lymphoma (LSA) is responsive to initial treatment, however, it then becomes resistant to drugs in the initial protocol. New rescue protocols are needed. HYPOTHESIS: A combination of L-asparaginase, lomustine, and prednisone will be well tolerated and efficacious as a rescue therapy for dogs with LSA. ANIMALS: Thirty-one client owned dogs with cytologically confirmed multicentric LSA who were refractory or whose disease had relapsed after a CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone)-based chemotherapy protocol. METHODS: Prospective clinical trial. Lomustine (target dose, 70 mg/m2) was administered orally at 3-week intervals for a total of 5 doses or until disease progression. L-asparaginase (400 U/kg) was administered subcutaneously concurrently with the first 2 lomustine treatments. Prednisone was administered at a tapering dose for the duration of the protocol. RESULTS: Overall response rate for dogs treated with this protocol was 87% (27/31), with 52% (16/31) of dogs achieving a complete response. Median time to response was 21 days. Median time to progression was 63 days (111 days for dogs achieving a complete response and 42 days for dogs achieving a partial response). There were no significant differences in response rates and times to progression between dogs who had received L-asparaginase before beginning this rescue protocol and those who had not. Toxicoses were mild and self-limiting in 29 of 31 cases. CONCLUSIONS AND CLINICAL IMPORTANCE: This is a well-tolerated rescue therapy for relapsing LSA in dogs. Response rates and remission durations compare favorably to other rescue protocols. Therefore, this protocol is a viable rescue option.     

Increased toxicity of P-glycoprotein-substrate chemotherapeutic agents in a dog with the MDR1 deletion mutation associated with ivermectin sensitivity

Lymphoma was diagnosed in a 4-year-old spayed female Collie, and treatment with a combination chemotherapy protocol incorporating prednisone, L-asparaginase, vincristine, vinblastine, doxorubicin, and cyclophosphamide was initiated. The dog had signs of gastrointestinal tract toxicosis and myelosuppression after treatment with P-glycoprotein-substrate drugs (vincristine, vinblastine, and doxorubicin) even when dosages were reduced, but did not have signs of toxicosis after treatment with cyclophosphamide, a non-P-glycoprotein-substrate drug, even when administered at the full dosage. It was postulated that a deletion mutation in the canine MDR1 gene (deltaMDR1 295-298) could be responsible for the drug toxicoses in this dog. This mutation has been identified as the cause of a functional P-glycoprotein defect in Collies susceptible to the toxic effects of ivermectin, another P-glycoprotein-substrate drug. The MDR1 genotype of this dog consisted of 1 normal and 1 mutant MDR1 allele. Because P-glycoprotein contributes to renal, biliary, and intestinal excretion of P-glycoprotein-substrate drugs, it is possible that drug excretion was delayed in this patient, resulting in clinical signs of toxicosis.     

Comparison of efficacy and toxicity of doxorubicin and mitoxantrone in combination chemotherapy for canine lymphoma

Forty-four dogs with multicentric lymphoma were treated using a cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) induction protocol or treated using a cyclophosphamide, mitoxantrone, vincristine, and prednisolone (CMOP) induction protocol. There was no statistical difference in signalment and the presence of historical negative prognostic factors between the groups. The median progression-free survival (PFS) in the CHOP and CMOP groups were 222 d and 162 d, respectively (P = 0.75). The median survival time (MST) of dogs in CHOP and CMOP groups were 318 d and 242 d, respectively (P = 0.63). Anorexia and diarrhea episodes were significantly higher in the CHOP group than in the CMOP group (P = 0.02 and P = 0.01, respectively). These results suggest that the CMOP protocol provides similar PFS, MST and causes fewer side effects compared to the CHOP protocol. Therefore, the CMOP protocol may be another treatment choice for canine multicentric lymphoma.     

Pseudolymphoma in a cat on phenobarbital treatment

A two‐year‐old female spayed domestic shorthair cat was presented with apathy, inappetence and generalised lymphadenomegaly. Anamnestic data included a generalised seizure disorder and phenobarbital treatment started one month before presentation. Routine blood analysis revealed only mild abnormalities and FeLV and FIV tests were negative. Both popliteal lymph nodes were aspirated and cytology was consistent with reactive lymph node hyperplasia. PCR for antigen receptor rearrangement testing diagnosed a polyclonal cell population. In the absence of another cause, lymphadenomegaly was attributed to an adverse drug reaction and phenobarbital was discontinued. The cat's condition improved and lymph node size normalised over the next 10 days. The retrospective diagnosis was phenobarbital‐induced pseudolymphoma.     

Feline extranodal lymphoma: response to chemotherapy and survival in 110 cats

O bjective : To determine response to treatment, survival and prognostic factors for feline extranodal lymphoma in the UK.
M ethods : Records of cats diagnosed with lymphoma of extranodal sites at seven referral centres were reviewed and information on signalment, tumour location, prior treatment and chemotherapy protocol recorded. Factors influencing response to treatment and survival were assessed.
R esults : One hundred and forty-nine cases met inclusion criteria. Sixty-nine cats had nasal lymphoma, 35 renal, 15 central nervous system, 11 laryngeal and 19 miscellaneous locations. Sixty-six cats received cyclophosphamide, vincristine, prednisolone, 25 Wisconsin-Madison doxorubicin-containing multi-agent protocol, 10 prednisolone alone and nine other combinations. The response rate for the 110 treated cats was 85·5 per cent. Of cyclophosphamide, vincristine, prednisolone treated cats 72·7 per cent achieved complete remission, median survival 239 days. Sixty-four per cent of Wisconsin-Madison treated cats achieved complete remission, median survival 563 days. Cats with nasal lymphoma achieving complete remission had the longest survival (749 days) and cats with central nervous system lymphoma the shortest (70 days). If complete remission was achieved, prior treatment with corticosteroids significantly reduced survival time.
C linical S ignificance : Cats with extranodal lymphoma respond to chemotherapy and achieve survival times comparable to other locations. Corticosteroid pretreatment reduced survival time in cats achieving complete remission.     

Evaluation of L-asparaginase: Polyethylene Glycol Conjugate Versus Native L-asparaginase Combined with Chemotherapy: A Randomized Double-blind Study in Canine Lymphoma

L-asparaginase is an enzyme that inhibits protein synthesis by the depletion of sources of L-asparagine, which is necessary for transformed lymphoid cells to proliferate. L-asparaginase is used in the treatment of childhood acute lymphoblastic leukemia. A problem with L-asparaginase therapy is the immunogenicity of the enzyme and the development of anaphylactic reactions. Canine lymphoma is a predominantly B-cell tumor with widespread disease; without treatment, dogs with lymphoma usually survive 1-2 months. Canine lymphoma will respond to L-asparaginase therapy. A randomized double-blind study evaluated a polyethylene glycol (PEG) conjugate L-asparaginase combined with chemotherapy (vincristine, cyclophosphamide, doxorubicin, and prednisone). Thirty-five dogs were randomized to the PEG L-asparaginase group, and 34 dogs were randomized to the native L-asparaginase group. Thirty dogs (85.7%) achieved a complete remission (CR) with a median time to relapse of 217 days, and 32 (94.1%) dogs in the native L-asparaginase group achieved a CR with a median time to relapse of 214 days (P greater than 0.05). The asparaginase was well tolerated in both groups. Two dogs in the native L-asparaginase group had severe allergic reactions, and one dog in the PEG asparaginase group had a generalized urticarial reaction after repeated injections. This study indicates that PEG L-asparaginase has equal therapeutic efficacy to native L-asparaginase.     

Tumor staging in a Beagle dog with concomitant large B-cell lymphoma and T-cell acute lymphoblastic leukemia

An 8-y-old spayed female Beagle dog was presented with peripheral lymphadenomegaly. Lymph node cytology and flow cytometry led to the diagnosis of large B-cell lymphoma (LBCL). We detected minimal percentages of LBCL cells in peripheral blood and bone marrow samples. However, a monomorphic population of neoplastic cells different from those found in the lymph node was found in the bone marrow. T-cell acute lymphoblastic leukemia was suspected based on flow cytometric immunophenotyping. PCR for antigen receptor rearrangement (PARR) revealed clonal rearrangement of both B-cell and T-cell receptors, and the presence of both neoplastic clones in the lymph node, peripheral blood, and bone marrow. The dog was treated with multi-agent chemotherapy but died 46 d following diagnosis. Tumor staging and patient classification are needed to accurately establish a prognosis and select the most appropriate therapeutic protocol.     

Evaluation of some prognostic factors for advanced multicentric lymphosarcoma in the dog: 147 cases (1978-1981)

A total of 147 dogs treated with a combination of chemotherapy procedure (vincristine, L-asparaginase, cyclophosphamide, and methotrexate) were evaluated for response to therapy and the influence of age, sex, clinical stage, and body weight to duration of response. Complete response was achieved in 113 dogs (77%), partial response in 26 dogs (17.7%), and no response in 8 dogs (5.4%). The median survival time for the dogs with complete and partial responses was 265 days. An analysis of factors associated with prognosis revealed that age, clinical stage, and body weight were not associated with response to therapy, whereas sex was. Females had a significantly prolonged remission and survival time (P = 0.0001).     

Treatment of canine lymphoma by veterinarians in first opinion practice in England

A survey of canine lymphoma treatment strategies by veterinarians in first opinion practice was undertaken by sending questionnaires to 1000 randomly selected, first opinion small animal veterinary practices throughout England. Completed replies were received from 382 veterinarians. Ninety-five per cent of respondents had diagnosed canine lymphoma in the preceding 12 months. Eighty-seven per cent of respondents treated at least 50 per cent of the cases of canine lymphoma they diagnosed. A multidrug combination of vincristine, cyclophosphamide and prednisolone (COP) was the treatment protocol most commonly used. A doxorubicin-based treatment protocol was used by 2 per cent of respondents to treat canine lymphoma initially. The study suggests that, despite several reports of improved survival times with doxorubicin-based protocols, most veterinarians in first opinion practice in England treat canine lymphoma with COP.     

Lymph node aspirate from a California wine-country dog

A 4-year-old, male Golden Retriever was presented to the Veterinary Medical Teaching Hospital at the University of California-Davis with a history of lethargy, inappetance, and vomiting. The patient had generalized lymphadenomegaly, marked thrombocytopenia, mild anemia, and moderate hypoalbuminemia. Moderate to marked histiocytic inflammation and lymphocytic-plasmacytic reactivity of the mesenteric, left popliteal, and right mandibular lymph nodes were diagnosed cytologically. Many macrophages contained granular to amorphous material of a uniform blue color, occasionally in morula formation, suggestive of rickettsial organisms. Exposure to raw trout was subsequently documented, leading to a presumptive diagnosis of salmon poisoning disease (SPD). The patient responded quickly to doxycycline therapy for the causative agent of SPD (Neorickettsia helminthoeca). SPD should be considered as a differential diagnosis for a canine patient with clinical signs of vomiting, diarrhea, lethargy, and lymphadenomegaly; laboratory findings of thrombocytopenia and hypoalbuminemia; and potential exposure to raw fish from an endemic area. The cytologic finding of rickettsial inclusions within lymph node macrophages is reportedly seen within a majority of SPD cases and can be valuable in supporting a clinical suspicion of SPD, as it was in this case.     

Prognostic variables in canine multicentric lymphosarcoma

This paper presents the results of a prospective study to investigate the prognostic value of clinical staging, histological grading, immunophenotype, mitotic count and average numbers of argyrophilic nucleolar organiser region counts in dogs with multicentric lymphosarcoma treated with a standard chemotherapy protocol comprising vincristine, cyclophosphamide and prednisolone. Forty-nine dogs were treated according to the study protocol. Univariate and multivariate analysis with regression modelling was used to evaluate the prognostic importance of patient and tumour variables upon tumour response and relapse-free survival. Thirty-seven dogs (76 per cent) achieved a complete remission, seven (14 per cent) a partial remission and five (10 per cent) failed to respond to treatment. None of the variables examined had a statistically significant effect upon tumour response. Tumour immunophenotype was the only parameter found to have a significant influence on patient survival, the hazard ratio for T-cell versus B-cell immunophenotype was 3.99 with 95 per cent confidence interval from 1.399 to 11.372, P = 0.035.     

Canine multicentric lymphoma 2: Comparison of response to two chemothera-peutic protocols

This paper describes the chemotherapeutic response of 90 cases of canine multicentric lymphoma. All the dogs were treated with a combination protocol using cyclophosphamide, vincristine and prednisolone. Forty-seven dogs received additional intravenous cytosine arabinoside on the first four days of treatment. Eighty-eight per cent of all cases had shown either a complete or partial response to this treatment at six weeks from the start of treatment and the overall mean survival time was 37 weeks (SD = 35.8). There was no significant difference in response or survival rates between the two treatment groups. The age and sex of the patient, the clinical stage of the disease and previous treatment with corticosteroids were all analysed to determine whether these parameters were of prognostic significance. Those dogs in clinical stages 4 and 5 carried a worse prognosis than those in stages 1 to 3. Previous treatment with corticosteroids adversely affected both tumour response and patient survival rates.     

Comparison of 3 protocols for treatment after induction of remission in dogs with lymphoma

BACKGROUND: The optimal treatment after inducing complete remission (CR) in dogs with lymphoma has not been established. HYPOTHESIS: After inducing CR with L-asparaginase, vincristine, cyclophosphamide, doxorubicin, prednisone (L-CHOP); consolidation with either half-body radiation therapy (HBRT); or lomustine (CCNU) and mechlorethamine, vincristine, procarbazine, prednisone (MOPP) would improve first remission duration compared with continuing a CHOP-based protocol for an additional 4 months. ANIMALS: Dogs with stage III-V lymphoma. METHODS: Prospective clinical trial in which dogs initially were treated with an 8-week induction protocol that consisted of L-CHOP. Dogs in CR after induction were then allocated to 1 of 2 consolidation arms. A chemotherapy consolidation arm consisted of 2 treatments with CCNU and 1 cycle of MOPP. A HBRT arm consisted of 2 sequential 8.0-Gy fractions to the cranial and caudal half-body separated by 30 days. Vincristine was given between fractions. Results of the consolidation arms also were compared with a historical group treated with the same 8-week induction protocol followed by CHOP therapy until week 24. RESULTS: Overall, 67% of the dogs were in CR after 8 weeks of induction chemotherapy and were compared. Fifty-two dogs were in the historical arm, 23 in the CCNU/MOPP arm, and 27 in the HBRT arm. No difference in first remission duration was found among groups. Median first remission duration for the historical, CCNU/MOPP, and HBRT arms were 307, 274, and 209 days, respectively (P = .28). Overall second CR rate was 82% and was not different among groups (all P > or = .58). Overall remission duration (P = .28) and survival time (P = .48) were not different among groups. CONCLUSIONS AND CLINICAL IMPORTANCE: Consolidation with either CCNU/MOPP or HBRT showed no advantage over a standard CHOP-based protocol.     

Evaluation of the results of a L-asparaginase-based continuous chemotherapy protocol versus a short doxorubicin-based induction chemotherapy protocol in dogs with malignant lymphoma.

The results of an L-asparaginase-based continuous chemotherapy protocol (n = 52) versus a short doxorubicin-based induction chemotherapy protocol (n = 65) were evaluated in 117 dogs with malignant lymphoma. There were no differences between the two groups in patient characteristics or incidence of protocol-related toxicity. Complete remission was induced in 71.2% of the dogs treated with the L-asparaginase protocol and in 67.7% of the dogs treated with the doxorubicin-plus protocol. The calculated Kaplan-Meier one- and two-year survival fractions in the L-asparaginase group were 48% and 26%, and in the doxorubicin-plus group 35%, and 22%, respectively. Differences in remission and survival between the two treatment groups were not significant. A multivariate Cox proportional hazards survival analysis revealed that elevated pretreatment plasma creatinine concentration and prior treatment with prednisolone were associated with shorter survival times. An elevated pretreatment plasma creatinine concentration and total leucocyte count were associated with a decrease in the disease-free period. Differences in efficacy and toxicity between the two protocols were not significant. There is no apparent advantage in using the continuous L-asparaginase protocol, and the shorter doxorubicin-plus protocol is less expensive and less time consuming.     

Computed tomography of a cat with primary intratracheal lymphosarcoma before and after systemic chemotherapy

A 12 yr old male neutered domestic shorthair cat presented with worsening tachypnea of 1 mo duration and open mouth breathing. Radiographs revealed tracheal narrowing at the thoracic inlet. Computed tomography (CT) revealed a contrast enhancing 8-cm long fusiform mass within the dorsal tracheal membrane. Tracheobronchoscopy confirmed the presence of the tracheal mass at the thoracic inlet, and lymphoma was diagnosed based on uniformly atypical lymphoid cells on aspirated bronchoalveolar lavage fluid. The cat was treated with combination chemotherapy consisting of cyclophosphamide, vincristine, doxorubicin, and prednisolone. Thoracic radiographs and CT performed 1 mo after completion of the 6 mo chemotherapy protocol revealed resolution of the tracheal mass. The cat remained clinically normal at 21 mo after treatment.