Serum amyloid A is not a marker for relapse of multicentric lymphoma in dogs

BACKGROUND: Serum amyloid A (SAA) is an acute phase protein whose concentration increases in inflammatory, infectious, and neoplastic conditions in animals and human beings. Multicentric lymphoma is a common cancer in dogs, and chemotherapy is indicated to attain long-term survival. However, frequent relapses lead to changes in chemotherapeutic protocols. OBJECTIVES: The aims of this study were to evaluate SAA as a marker for relapse of multicentric lymphoma in dogs and to determine whether chemotherapy induces changes in the concentration of SAA during treatment. METHODS: SAA was measured by an ELISA test in healthy control dogs (n=20), in healthy dogs receiving chemotherapy (n=8), and in dogs with lymphoma (n=20). All dogs receiving chemotherapy were randomly assigned to 2 treatment groups, one receiving cyclophosphamide, vincristine, and prednisone (CVP) and the other receiving vincristine, cyclophosphamide, methotrexate, and L-asparaginase (VCMA) protocols. SAA concentration was determined before chemotherapy at weeks 1-4 in healthy dogs receiving chemotherapy and in dogs with lymphoma, then every 3 weeks for 4 months in healthy dogs, and at relapse and in the sample prior to relapse in dogs with lymphoma. SAA was measured only once in the healthy control dogs. Results were analyzed using repeated measures ANOVA followed by Tukey multiple comparison tests to compare groups and weeks of treatment. RESULTS: Mean SAA concentration was significantly higher in dogs with lymphoma before chemotherapy compared with healthy and chemotherapy control dogs. No increase in SAA concentration was found at relapse. No differences were observed in SAA concentration based on type of chemotherapy protocol. CONCLUSIONS: SAA is not a marker of relapse in dogs with multicentric lymphoma, nor does chemotherapy regimen affect SAA concentration.     

Serum alpha 1-acid glycoprotein concentrations before and after relapse in dogs with lymphoma treated with doxorubicin

OBJECTIVE: To determine whether serum alpha 1-acid glycoprotein (AGP) concentration was a useful marker of relapse in dogs with lymphoma that were in clinical remission following treatment with doxorubicin. DESIGN: Cohort study. ANIMALS: 12 dogs with lymphoma and 10 healthy dogs. PROCEDURE: Serum AGP concentration was measured in the healthy dogs and in the dogs with lymphoma before treatment, 3 weeks after the first dose of doxorubicin was administered, and every 3 weeks thereafter until relapse (i.e., recurrence of clinically detectable disease such as palpable enlargement of peripheral lymph nodes). Serum AGP concentrations were determined by use of a radial immunodiffusion kit. RESULTS: Mean serum AGP concentration in healthy dogs was significantly less than concentration in dogs with lymphoma prior to treatment. Mean serum AGP concentrations after the first and each subsequent dose of doxorubicin were not significantly different from concentration in healthy dogs. However, mean serum AGP concentrations 3 weeks prior to and at the time of relapse were significantly higher than concentration measured after the first dose of doxorubicin, and were not significantly different from concentration measured before treatment. CLINICAL IMPLICATIONS: Results suggest that measuring serum AGP concentration may be a useful method of predicting relapse before recurrence of clinically detectable disease in dogs with lymphoma undergoing treatment with doxorubicin.     

Serum C-reactive protein concentration as an indicator of remission status in dogs with multicentric lymphoma

BACKGROUND: The acute-phase protein C-reactive protein (CRP) is used as a diagnostic and prognostic marker in humans with various neoplasias, including non-Hodgkin's lymphoma. OBJECTIVE: To evaluate if CRP could be used to detect different remission states in dogs with lymphoma. ANIMALS: Twenty-two dogs with untreated multicentric lymphoma. METHODS: Prospective observational study. Blood samples were collected at the time of diagnosis, before each chemotherapy session, and at follow-up visits, resulting in 287 serum samples. RESULTS: Before therapy, a statistically significant majority of the dogs (P = .0019) had CRP concentrations above the reference range (68%, 15/22). After achieving complete remission 90% (18/20) of the dogs had CRP concentrations within the reference range, and the difference in values before and after treatment was statistically significant (P < .001). CRP concentrations of dogs in complete remission (median, 1.91; range, 0.2-103) were significantly different (P = .031) from those of dogs with partial remission (median, 2.48; range, 0-89), stable disease (median, 1.77; range, 1.03-42.65), or progressive disease (median, 8.7; range, 0-82.5). There was profound variation of CRP measurements within each dog. CONCLUSIONS: CRP is useful in determining complete remission status after treatment with cytotoxic drugs. However, the individual variation between dogs means CRP concentration is not sufficiently different in other remission states to permit its use in monitoring progression of the disease. Greater reliability in determining remission status might be achieved by combining CRP concentration with other serum markers.     

Asparaginase and MOPP Treatment of Dogs with Lymphoma

Background: Dogs with multicentric lymphoma are treated with various cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based chemotherapy protocols with variable success.
Objectives: To describe the progression-free survival (PFS) time and overall survival time (OST) of dogs with T-cell lymphoma or hypercalcemic lymphoma treated with l -asparaginase and mechlorethamine, vincristine, prednisone, procarbazine (MOPP).
Animals: Fifty dogs with T-cell lymphoma, hypercalcemic lymphoma, or both treated at 3 referral veterinary hospitals.
Methods: Retrospective study. Case were selected based on histologic or cytologic diagnosis of lymphoma; presence of the T-cell phenotype, presence of hypercalcemia or both; and absence of previous chemotherapy. The T-cell phenotype was determined by flow cytometry, immunocytochemistry, immunohistochemistry, or polymerase chain reaction of antigen receptor rearrangement.
Results: The overall response rate was 98% (78% complete response, 20% partial response). The median PFS for the entire study population was 189 days with 25% PFS at 939 days. The median OST for the entire study population was 270 days with 25% surviving 939 days. Twenty percent of the dogs required hospitalization for treatment related complications.
Conclusions and clinical importance: l -Asp/MOPP chemotherapy might result in longer PFS and OST for dogs with multicentric T-cell lymphoma, dogs with hypercalcemic lymphoma or both, than achieved with CHOP.     

CHOP chemotherapy for the treatment of canine multicentric T-cell lymphoma

Dogs with multicentric T-cell lymphoma are commonly treated with CHOP chemotherapy protocols that include cyclophosphamide, doxorubicin, vincristine and prednisone. The purpose of this study was to evaluate the use of CHOP chemotherapy for dogs with multicentric T-cell lymphoma. Identification of prognostic factors in this specific subset of dogs was of secondary interest. Twenty-three out of 24 dogs responded to CHOP chemotherapy and these dogs remained on the protocol for a median of 146 days. No variable was associated with progression free survival (PFS) including stage, substage, hypercalcemia or radiographic evidence of a cranial mediastinal mass. The median overall survival time (OST) for all dogs was 235 days. Dogs that were thrombocytopenic at presentation experienced a significantly longer OST (323 versus 212 days, P=0.01).     

Increased monocyte chemotactic protein-1 concentration and monocyte count independently associate with a poor prognosis in dogs with lymphoma

Overexpression of the chemokine monocyte chemotactic protein-1 (MCP-1) has been associated with a poor prognosis in many human cancers. Increased MCP-1 concentrations may promote tumour progression by increasing mobilization of myeloid derived suppressor cells such as immature monocytes and neutrophils. We hypothesized that increased numbers of peripheral neutrophils or monocytes and increased MCP-1 concentrations would predict a worse outcome in dogs with multicentric lymphoma. In this retrospective study involving 26 client-owned dogs diagnosed with lymphoma, we show that peripheral neutrophil and monocyte counts as well as serum MCP-1 concentrations were significantly elevated relative to healthy control animals, and that such increases were associated with a decreased disease-free interval in dogs treated with chemotherapy based on cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP). To our knowledge, this is the first study showing that pretreatment evaluation of monocyte and neutrophil counts can provide important prognostic information in dogs with lymphoma. The mechanisms underlying these observations remain to be determined.     

Comparison of COAP and UW-19 protocols for dogs with multicentric lymphoma

BACKGROUND: Various chemotherapy protocols for treating lymphoma in dogs have been published; however, comparison of protocols from different studies is difficult, especially when evaluating survival time and toxicoses. HYPOTHESIS: The choice of COAP (C, cyclophosphamide; O, vincristine; A, cytosine arabinoside; P, prednisone) and a modified University of Wisconsin 19-week (UW-19) induction protocol has no influence on overall survival times in dogs with lymphoma. ANIMALS: One hundred and one dogs with multicentric lymphoma. METHODS: Retrospective study (2001-2006). Dogs induced with either an 8-week COP-based protocol (C, cyclophosphamide; O, vincristine; and P, prednisone) with maintenance therapy (COAP group) or a 19-week CHOP (C, cyclophosphamide; H, doxorubicin; O, vincristine; and P, prednisone) based protocol (UW-19 group) were compared in terms of the duration of first remission, survival time, toxicoses, and cost. RESULTS: There were 71 dogs in the COAP group and 30 dogs in the UW-19 group. Various protocols were used after the first relapse. The median duration of the first remission for the COAP and UW-19 groups were 94 days (range, 6-356 days) and 174 days (28-438 days), respectively (P < .01). The median survival times for dogs in the COAP and UW-19 groups were 309 days (6-620 days) and 275 days (70-1102+ days), respectively (P = .09). Dogs in the COAP group had a hazard ratio of 1.9 (95% CI 1.1-3.4) for death relative to the UW-19 group (P = .03), after controlling for the confounders (World Health Organization clinical stage, age, sex, use of doxorubicin during reinduction). The severity of neutropenia and gastrointestinal toxicoses were significantly higher in the UW-19 group than in the COAP group (P = .01 and P < .01, respectively). CONCLUSION AND CLINICAL IMPORTANCE: Use of a long-term doxorubicin-containing sequential combination chemotherapy protocol is associated with a decreased risk of relapse and death relative to a non-doxorubicin-containing protocol.     

Acute tumour lysis syndrome in a dog with B-Cell multicentric lymphoma

A 5-year-old, spayed female German Shepherd dog was admitted to hospital with marked generalised lymphadenomegaly and splenomegaly. A stage Va B-cell multicentric lymphoma was diagnosed on clinical, cytological (lymph node, bone marrow), histological-immunohistochemical (lymph node excision) and imaging grounds. Since no satisfactory remission was achieved using a multi-drug chemotherapy protocol that included cyclophosphamide, vincristine, cytosine arabinoside, prednisolone, and subsequently supplemented by L-asparaginase, it was replaced by another protocol combining vincristine, L-asparaginase, prednisolone, cyclophosphamide and doxorubicin. Soon after the third weekly session of the second protocol, the clinical status of the animal deteriorated suddenly and severely, with a bleeding tendency, jaundice, hyperuricaemia, hyperphosphataemia, azotaemia, hyperbilirubinaemia and, presumptive disseminated intravascular coagulation. There was also complete regression of lymphadenomegaly. This report emphasises the clinicopathological features and the diagnostic peculiarities of the acute tumour lysis syndrome, which occurs uncommonly in dogs.     

Evaluation of Single-Agent Mitoxantrone as Chemotherapy for Relapsing Canine Lymphoma

Many chemotherapeutic regimens will induce remission in dogs with lymphoma, but almost all dogs suffer relapse. Mitoxantrone was selected for evaluation as single-agent chemotherapy for relapsing canine lymphoma based on its use in humans undergoing salvage chemotherapy for non-Hodgkin's lymphoma and its tumoricidal effect against canine lymphoma. Dogs entered into study had multicentric lymphoma, and all had been treated solely with a standard combination chemotherapy protocol. At 1st relapse, all dogs were again staged and underwent lymph node biopsy. Mitoxantrone was administered IV at 6 mg/m² every 21 days. Dogs were evaluated for lymphadenopathy before each dose of mitoxantrone. Fifteen dogs were entered into study. The average age (±SEM) of the dogs studied was 7.7 ± 0.91 years, and most dogs were large (mean ± SEM weight, 24.44 ± 2.15 kg). Twelve dogs (80%) had B-cell lymphoma, and 3 had T-cell lymphoma. Dogs were staged IV (n = 12) or V (n = 3). The median duration of chemotherapy before entry into the study was 98 days. Overall median duration of response after mitoxantrone chemotherapy was 21 days. Complete responses were attained in 7 of 15 dogs (47%) with a median response duration of 84 days. Nine of 15 (60%) dogs attained a complete remission with additional chemotherapy after failing mitoxantrone chemotherapy. Mild toxicities were observed after mitoxantrone administration. No adverse reactions were observed during mitoxantrone infusions. The results of this study demonstrate that mitoxantrone, as a single agent, has limited value for dogs with lymphoma at 1st relapse after conventional multidrug chemotherapy.     

Drug Residues in Serum of Dogs Receiving Anticancer Chemotherapy

Background: The presence of drug residues in blood samples can represent an occupational hazard. However, studies on cytotoxic drug residues in serum of dogs are lacking in veterinary oncology. Objective: To evaluate possible occupational hazards associated with handling of blood samples from dogs receiving oncolytic drugs 7 days after treatment. Animals: Twenty‐seven client‐owned dogs treated for lymphoma or mast cell tumors with vincristine, vinblastine, cyclophosphamide, or doxorubicin. Methods: Prospective, observational study. Serum samples were either taken 7 days after administration of vincristine, cyclophosphamide, doxorubicin (lymphoma), and vinblastine (mast cell tumor), or 1–2 days after the last concurrent oral administration of cyclophosphamide (mast cell tumor). Additionally, serum was collected within 5 minutes of treatment. Measurement of drug residues in serum was performed by liquid chromatography tandem mass spectrometry (LC/MS/MS). Results: In 33 samples collected within 5 minute of treatment, the median serum concentrations were vincristine: 37 μg/L (range: 11–87 μg/L), vinblastine: 13 μg/L (range: 13–35 μg/L), cyclophosphamide: 2,484 μg/L (range: 1,209–2,778 μg/L), doxorubicin: 404 μg/L (range: 234–528 μg/L). In 81 serum samples collected 7 days after treatment vinblastine (7 μg/L) was detected in 1 sample, and cyclophosphamide (7 and 9 μg/L) in 2 samples collected 1–2 days after oral administration of cyclophosphamide. Medications were not detected in any of the other samples. Conclusions and Clinical Importance: Handling of blood samples from dogs receiving oncolytic chemotherapy 7 days after treatment with vincristine, vinblastine, cyclophosphamide, and doxorubicin should not present a health hazard.     

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.     

Alpha-fetoprotein in Canine Multicentric Lymphoma

The concentrations of AFP were evaluated in the sera from groups of healthy dogs and of dogs with multicentric lymphoma, before and while receiving chemotherapy. The concentration of AFP was highest in the affected dogs, especially during the fifth stage of lymphoma. Chemotherapy caused a decrease in AFP serum concentration, during both the induction and the maintenance phases of treatment, when compared to the same animals before therapy. Determination of the concentration of AFP in the serum may be an additional indicator in the evaluation of the stage of lymphoma, and of value in assessing the extent of neoplastic infiltration of the liver.     

Is Maintenance Chemotherapy Appropriate for the Management of Canine Malignant Lymphoma?

A retrospective study was conducted between two groups of dogs with histopathologically diagnosed multicentric malignant lymphoma to determine if treatment with either short-term or continuous chemotherapy resulted in a significant difference in first-remission length or survival time. One group was treated with single agent, short-term (three cycles) of doxorubicin. Dogs obtaining complete remission while receiving doxorubicin were given no further chemotherapy. The other group received combination agent, long-term chemotherapy consisting of cyclophosphamide, vincristine sulfate, and prednisone (COP). Dogs obtaining complete remission on COP by the end of 6 weeks were given maintenance chemotherapy of cyclophosphamide, prednisone and methotrexate. One hundred and five dogs were treated. Thirty-eight dogs received doxorubicin and 67 received COP. All dogs were evaluated at 6 weeks for response to chemotherapy and followed until death. No significant differences were observed in first-remission length or survival time when comparing dogs treated with either short-term doxorubicin or long-term COP (P greater than 0.05). Sex, weight, age, clinical stage, performance status, histopathologic cell type, and grade were not significant factors for determining the responsiveness to either chemotherapy protocol. However, within either treatment group, significant differences in first-remission length were observed in dogs evaluated histopathologically by the Keil and NCI working formulation and in survival time when evaluated by performance status (P less than 0.05).     

Assessment of anemia as an independent predictor of response to chemotherapy and survival in dogs with lymphoma: 96 cases (1993-2006)

OBJECTIVE: To determine whether the presence of anemia (Hct < or = 37%) at the time of diagnosis of lymphoma is a negative prognostic indicator for response to treatment and survival time in dogs that are undergoing chemotherapy. DESIGN: Retrospective case series. Animals-96 dogs with lymphoma that were receiving chemotherapy. Procedures-Information regarding signalment, initial hematologic data, chemotherapy protocol, clinical response, and date of death was retrospectively collected from medical records of dogs with lymphoma. Univariate, multivariate, and survival analyses were performed to determine the effect of anemia on initial response to chemotherapy and on survival time. RESULTS: Overall, dogs without anemia (n = 56) were 4 times as likely as dogs with anemia (40) to have a complete response following chemotherapy. Anemic dogs had a significantly shorter median survival time (139 days), compared with survival time of nonanemic dogs (315 days). Subset analysis of dogs with multicentric lymphoma (matched for clinical stage and chemotherapy protocol) revealed that the dogs with anemia (n = 24) had a significantly shorter median survival time (101 days), compared with survival time of dogs without anemia (24; 284 days). Other variables were not associated with survival time. CONCLUSIONS AND CLINICAL RELEVANCE: These findings suggested that anemia is a negative prognostic factor for dogs with lymphoma that are undergoing chemotherapy. Further investigation will be necessary to determine the impact of resolution of anemia on clinical outcome in dogs with lymphoma.     

Comparison of the effects of asparaginase administered subcutaneously versus intramuscularly for treatment of multicentric lymphoma in dogs receiving doxorubicin

OBJECTIVE: To determine the effectiveness and safety of asparaginase administered s.c. versus i.m. for treatment of multicentric lymphoma in dogs receiving doxorubicin. DESIGN: Prospective study. ANIMALS: 49 dogs with multicentric lymphoma. PROCEDURE: Dogs were treated with doxorubicin every 3 weeks, for a total of 5 treatments, and were given 3 weekly treatments of asparaginase, s.c. or i.m. Using high-performance liquid chromatography, mean plasma asparagine, aspartic acid, glutamine, and glutamic acid concentrations were determined in dogs before and during treatment with asparaginase (10,000 U/m2 of body surface area, once a week for 3 weeks). Asparaginase was administered s.c. in 23 dogs and i.m. in 26 dogs. Variables evaluated included time to response to chemotherapy, remission and survival times, and clinical and serum biochemical indicators of toxicoses. RESULTS: Using the World Health Organization's staging system for lymphoma, 30 dogs were in clinical stage III and 19 were in clinical stage IV. One week after asparaginase treatment, plasma asparagine concentrations were low and plasma aspartic acid, glutamine, and glutamic acid concentrations were high. Differences in plasma amino acid concentrations were not found between s.c. and i.m. groups. For dogs in clinical stage IV, i.m. administration of asparaginase significantly decreased the number of days to complete remission, compared with s.c. administration (8 vs 17 days, respectively). For dogs in clinical stage III, i.m. administration favorably increased the duration of first remission (191 vs 103 days) and survival time (289 vs 209 days). Overall, dogs treated i.m. had a faster response to chemotherapy (9 vs 15 days), a longer remission (191 vs 109 days), and a longer survival time (286 vs 198 days), compared with all dogs treated s.c. Asparaginase toxicoses were not observed regardless of the route of administration. CLINICAL IMPLICATIONS: For dogs with multicentric lymphoma that are receiving doxorubicin, i.m. treatment with asparaginase is more effective than s.c. treatment.     

Evaluation of a multidrug chemotherapy protocol with mitoxantrone based maintenance (CHOP-MA) for the treatment of canine lymphoma

The purpose of this study was to evaluate the efficacy of adding mitoxantrone to a cyclophosphamide, doxorubicin, vincristine, l -asparaginase and prednisone containing protocol. Sixty-five dogs with multicentric lymphoma were evaluated for overall remission and survival times. Remission and survival time versus stage, substage, pretreatment hypercalcaemia and pretreatment steroid administration were also evaluated. Overall median remission for dogs with multicentric lymphoma was 302 days and overall median survival was 622 days. Of the dogs with multicentric lymphoma, 23 (35%) received all scheduled mitoxantrone doses. Only median survival versus substage was found to be significant (substage a median survival was 679 days and substage b median survival was 302 days, P = 0.025). Increasing the total combined dose of doxorubicin and mitoxantrone may improve remission times when compared with historical controls, and further studies are needed to determine how best to utilize mitoxantrone in multidrug chemotherapy protocols for canine multicentric lymphoma.     

Serum thymidine kinase 1 activity as a prognostic biomarker in dogs with chemotherapy-treated diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is frequently treated with chemotherapy incorporating cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), which induces remission in 80% to 95% of cases. However, not all dogs derive meaningful benefit from CHOP, and prognostic factors for dogs with DLBCL are poorly defined. Serum thymidine kinase 1 (TK1) activity, a marker of tumour cell proliferation, has shown promising initial results as a prognostic biomarker in dogs with multicentric lymphomas. The purpose of this study was to determine if baseline serum TK1 activity is associated with clinical outcome in dogs with CHOP-treated DLBCL. Baseline serum TK1 activity was measured in banked sera from 98 dogs with CHOP-treated DLBCL using a commercially available ELISA kit. Data on other potential prognostic factors were abstracted retrospectively from electronic medical records. Multivariable statistical methods were used to identify associations between TK1 and other potential prognostic factors with progression-free survival (PFS) and attainment of complete remission. TK1 activity at baseline was not associated with PFS (p = .299) or attainment of complete remission (p = .910) following CHOP chemotherapy. Of the other prognostic factors analysed, only purebred (vs. mixed breed) status (HR 8.81, 95% CI 1.68–46.30, p = .010), attainment of complete (vs. partial) remission (HR 0.09, 95% CI 0.02–0.49, p = .006), and baseline serum C-reactive protein concentration (HR 1.19, 95% CI 1.07–1.32, p = .001) were independently associated with PFS. Based on these findings, baseline serum TK1 activity does not appear to be a useful prognostic biomarker in dogs with CHOP-treated DLBCL.     

Evaluation of serum interleukin 2 receptor and beta-2-microglobulin as prognostic factors for canine lymphoma: A pilot study

Interleukin 2 receptor (IL-2R) is released from activated T cell lymphocytes and related to proliferation of B cells and T cells. Beta-2-microglobulin (B2M) is synthesized from all nucleated cells and constitutes a major histocompatibility complex class I antigen. In human medicine, high concentrations of these two factors have been found to be related to prognosis in aggressive non-Hodgkin's lymphoma. In this pilot study, we aimed to assess the correlation between the serum concentration of IL-2R and B2M and the diagnosis and prognosis of canine lymphoma. This study included 8 healthy dogs and 17 dogs with lymphoma. To measure the serum concentration of IL-2R and B2M, a commercial enzyme-linked immunosorbent assay was used. In dogs with lymphoma, IL-2R concentrations were significantly high at the time of diagnosis, but B2M concentrations were not. In relapsed dogs, both IL-2R and B2M concentrations were significantly higher than those in the control and chemotherapy response groups. When the serum concentrations of IL-2R and B2M during chemotherapy were monitored in four relapsed dogs, B2M levels were more closely related with relapse. This study demonstrated that serum IL-2R and B2M concentration can be a diagnostic or prognostic tool for canine lymphoma. Monitoring of serum B2M concentration seems to be useful for predicting relapse.     

Increase in minimal residual disease in peripheral blood before clinical relapse in dogs with lymphoma that achieved complete remission after chemotherapy

Background: We developed previously a minimal residual disease (MRD) monitoring system in dogs with lymphoma by exploring a highly sensitive real‐time PCR system. Objectives: To identify the change in MRD before clinical relapse in dogs with lymphoma that achieved complete remission after chemotherapy. Animals: Twenty dogs with multicentric high‐grade B‐cell lymphoma. Methods: MRD levels in peripheral blood mononuclear cells (PBMCs) were measured by real‐time PCR amplifying the rearranged immunoglobulin heavy chain gene. MRD measurement and clinical assessment were performed every 2–4 weeks for 28–601 days after completion of chemotherapy. An increase in MRD was defined as an increase by more than 0.5, calculated by log₁₀[copy number of MRD per 10⁵ PBMCs], based on the uncertainty level observed in a canine lymphoma cell line. Results: During the follow‐up period, 15 dogs relapsed in 28–320 days (median, 120 days) after completion of chemotherapy. An increase in MRD was detected 2 weeks or more before relapse in 14 of the 15 dogs, but an increase in MRD before relapse could not be detected in the remaining 1 dog. The time from increased MRD to clinical relapse was 0–63 days (median, 42 days). In contrast, no increase in MRD was detected in 5 dogs that did not experience clinical relapse. Conclusion and Clinical Importance: An increase in MRD can be detected before clinical relapse in dogs with lymphoma. Application of early reinduction therapy based on an increase in MRD before clinical relapse may improve treatment outcome in canine lymphoma.     

Evaluation of a multi‐agent chemotherapy protocol combining lomustine,procarbazine and prednisolone (LPP) for the treatment of relapsed canine non‐Hodgkin high‐grade lymphomas

The standard of care treatment for canine lymphoma is multi‐agent chemotherapy containing prednisolone, cyclophosphamide, vincristine and an anthracycline such as doxorubicin (CHOP) or epirubicin (CEOP). Lomustine, vincristine, procarbazine, and prednisone (LOPP) has been evaluated as a rescue, with encouraging results; however, resistance to vincristine is likely in patients relapsing on CHOP/CEOP, and this agent may enhance LOPP toxicity without improving efficacy. The aim of this study was to evaluate responses to a modified‐LOPP protocol that does not include vincristine (LPP) and is administered on a 21‐day cycle. Medical records of dogs with high‐grade multicentric lymphoma from 2012 to 2017 were reviewed. Dogs with relapsed lymphoma that received LPP as a rescue protocol were enrolled. Response, time from initiation to discontinuation (TTD) and toxicity of LPP were assessed. Forty‐one dogs were included. Twenty‐five dogs (61%) responded to LPP including 12 complete responses (CR) and 13 partial responses (PR). Responders had a significantly longer TTD (P < .001) compared to non‐responders with 84 days for CR and 58 days for PR. Neutropenia was documented in 20 dogs (57%): 12 grade I to II, 8 grade III to IV. Thrombocytopenia was infrequent (20%): 5 grade I to II, 2 grade III to IV. Twelve dogs developed gastrointestinal toxicity (30%): 10 grade I to II and 2 grade III. Nineteen dogs had elevated ALT (59%): 9 grade I to II, 10 grade III to IV. Treatment was discontinued due to toxicity in 8 dogs (19%). The LPP protocol shows acceptable efficacy and toxicity‐profile and minimizes in‐hospital procedures.