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.     

Evaluation of a Multidrug Chemotherapy Protocol (ACOPA II) in Dogs With Lymphoma

A chemotherapeutic protocol using cyclophosphamide, vincristine, prednisone, doxorubicin, and L-asparaginase (ACOPA II) was evaluated in dogs with lymphoma. The response rate for 68 dogs treated with ACOPA II (complete remission [CR] 65%, partial remission [PR] 10%) was lower than that for 41 dogs treated with a related protocol previously evaluated (ACOPA I; CR 76%, PR 12%). Initial treatment with doxorubicin and prednisone did not decrease the prevalence or severity of toxicity during induction. The mortality during induction was 22%. The median duration of CR for dogs treated with ACOPA II was 9 months, with 40% still in remission at 1 year and 21% at 2 years. The rate of CR was lower for dogs with signs of illness at presentation (substage b ) and for dogs weighing less than 15 kg. Age was negatively correlated with survival time and duration of remission. Dogs with immunoblastic lymphoma had a more favorable prognosis than did those with lymphoblastic lymphoma. Survival times were also longer for dogs in substage a at presentation. Seven dogs in which treatment was discontinued while in remission had comparable remission duration to that achieved by dogs receiving long-term maintenance chemotherapy.     

Combination of CCNU and DTIC chemotherapy for treatment of resistant lymphoma in dogs

BACKGROUND: Pleotropic-glycoprotein (P-gp)-mediated resistance is the usual cause of relapse in dogs with lymphoma. 1-(2-chloroethyl)3-cyclohexyl-1-nitrosurea (CCNU) and 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) are alkylating agents that are not affected by P-gp and lack cross-resistance to each other. A combination protocol offers the advantage of improved summation dose and synergistic activity. HYPOTHESIS: A combination of CCNU and DTIC that is well tolerated can be used to treat dogs with lymphoma that developed resistance or failed to respond to previously administered chemotherapy. ANIMALS: Fifty-seven dogs with lymphoma that were resistant to treatment with standard chemotherapy (L-CHOP; L-asparaginase, cyclophosphamide, doxorubicin, vincristine, prednisone). METHODS: Prospective phase I and II trials were performed. CCNU was given PO immediately before a 5-h IV infusion of DTIC. Concurrent antiemetics and prophylactic antibiotics were used. Treatments were administered every 4 weeks. RESULTS: Based on the results of 8 dogs in the phase I study, CCNU at 40 mg/m(2) PO combined with DTIC at 600 mg/m(2) IV was used to treat 57 dogs with resistant lymphoma. Thirteen (23%) dogs had a complete response (CR) for a median of 83 days and 7 (12%) had a partial response for a median of 25 days. The median L-CHOP CR duration of the dogs that did not respond to CCNU-DTIC was significantly longer than that of the dogs that did achieve remission with CCNU-DTIC (225 days versus 92 days, P= .02). The principal toxic event was neutropenia; the median neutrophil count 7 days after treatment was 1,275 cells/microL. Increases in alanine transaminase activity, possibly associated with hepatotoxicity, were detected in 7 dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: A combination of CCNU and DTIC can be an effective option to rescue dogs with resistant lymphoma.     

A pilot study evaluating changes in pancreatic lipase immunoreactivity concentrations in canines treated with L-asparaginase (ASNase), vincristine, or both for lymphoma

L-asparaginase (ASNase) is a common chemotherapy agent for the treatment of lymphoid malignancies. L-asparaginase has been reported to cause clinical pancreatitis in both humans and canines. Canine pancreatic lipase immunoreactivity (cPLI) is now a common diagnostic tool for evaluating pancreatitis in dogs. A total of 52 dogs were enrolled into this study. Canine pancreatic lipase immunoreactivity (cPLI) concentrations were evaluated before and after administration of ASNase, vincristine, or both. All dogs enrolled in the study were evaluated for signs compatible with clinical pancreatitis. No dogs receiving ASNase alone showed evidence of clinical pancreatitis after administration. Also, there was no statistically significant change in cPLI concentrations before or after treatment. Fourteen percent of dogs that received both vincristine and ASNase concurrently had elevated concentrations of cPLI after treatment. Of the 11 dogs with clinical signs compatible with pancreatitis after any chemotherapy treatment, no dog had a cPLI concentration > 400 μg/dL. In conclusion, ASNase did not cause clinical pancreatitis in this cohort of dogs but larger sample sizes are required to further validate this data.     

Effects of single-dose L-asparaginase on coagulation values in healthy dogs and dogs with lymphoma.

Ten healthy dogs and 10 dogs with multicentric lymphoma were given a single dose of L-asparaginase at a rate of 10,000 IU/m2 of body surface. Assessment of concentrations of contributors to the coagulation process and of the ability to coagulate including antithrombin III, one-stage prothrombin time, prothrombin-proconvertin time, activated partial thromboplastin time, plasminogen, fibrinogen, and platelet number were performed prior to drug administration (day 0). These tests were repeated 24 hours (day 1), 48 hours (day 2), and 7 days after treatment with L-asparaginase. Antithrombin-III concentrations were significantly lower in the dogs with lymphoma than in healthy dogs on days 0, 1, 2, and 7; however, with the exception of day 1, mean values remained within normal limits. There was also a difference between the 2 groups in prothrombin/proconvertin values on day 7 and in platelet number on day 2, with the lymphoma group having significantly shorter prothrombin/proconvertin time than healthy dogs, and the difference in platelet numbers being associated with increased counts in the healthy dogs. Data obtained from the healthy dogs and dogs with lymphoma for each coagulation test were pooled for each treatment day (0, 1, 2, and 7), and day-0 values for each coagulation test were compared with data obtained on days 1, 2, and 7. Antithrombin-III concentration on day 7 was significantly lower than on day 0, prothrombin/proconvertin time on day 1 was significantly longer than on day 0, and fibrinogen concentrations on days 1 and 2 were significantly lower than on day 0.(ABSTRACT TRUNCATED AT 250 WORDS)     

Proof-of-concept study: Evaluation of plasma and urinary electrolytes as markers of response to L-asparaginase therapy in dogs with high-grade lymphoma

Response to chemotherapy is one of the most important prognostic factors in dogs with lymphoma. The objective of this feasibility study was to evaluate if clinical responses to a specific cytotoxic agent (L-asparaginase) could be anticipated by measuring analyte concentrations in plasma and urine concentrations of lymphoma-bearing dogs. We hypothesized that potassium and phosphate concentrations in plasma and urine would be higher in dogs that completely responded to therapy. Plasma and urine samples of dogs with lymphoma were obtained before 12 and 24 hours after intramuscular L-asparaginase injections. Peripheral lymph node volumes were evaluated according to the Veterinary Cooperative Oncology Group standardized criteria. Plasma and urine electrolyte, calcium, phosphate, creatinine, urea, total protein, and albumin concentrations were measured, and the fractional excretions of each electrolyte were calculated. Statistical analyses compared complete vs partial responders using a linear regression model. Contrast analyses were also performed to differentiate the mean of each group, with adjustments made with the Benjamini-Hochberg procedure. Fourteen dogs were included, eight with complete responses, and six with partial responses. Plasma phosphate concentrations were significantly higher at 12 hours (P = .0003) and 24 hours (P = .009) after complete responses to therapy. This study demonstrates the potential use of plasma and urine analyte monitoring after chemotherapy induction. Plasma phosphate measurements represent a potential indicator of early responses to L-asparaginase therapy. Larger population studies are warranted to confirm these preliminary results.     

Comparison between L-CHOP and an L-CHOP protocol with interposed treatments of CCNU and MOPP (L-CHOP-CCNU-MOPP) for lymphoma in dogs

An L-CHOP protocol with interposed treatments of CCNU and MOPP (L-CHOP-CCNU-MOPP) was evaluated in 66 dogs with stages III-V lymphoma. Results were compared with a historical group of 71 dogs treated with an L-CHOP protocol. Complete remission (CR) rates (85 and 80%, respectively) did not differ significantly between protocols (P = 0.48). First CR duration for dogs treated with L-CHOP-CCNU-MOPP was significantly longer: median, 317 days; 2-year CR rate, 35% versus median, 298 days; 2-year CR rate, 13%, P = 0.05). For the L-CHOP-CCNU-MOPP protocol, dogs in substage-b had a 4.3 times greater hazard of having a relapse than dogs in substage-a (P = 0.002). Frequency of adverse chemotherapy-associated gastrointestinal effects did not differ between protocols (P = 0.77). Neutropenia (primarily after CCNU) occurred more frequently in dogs treated with L-CHOP-CCNU-MOPP (P < 0.001). In summary, the L-CHOP-CCNU-MOPP protocol showed an improved duration of first CR as compared with an L-CHOP protocol, but the relevance of this finding might be subject to clinical judgement.     

Serum C-reactive protein concentrations in dogs with multicentric lymphoma undergoing chemotherapy

OBJECTIVE: To determine whether serum C-reactive protein (CRP) concentration is high in dogs with multicentric lymphoma, whether CRP concentration changes in response to chemotherapy, and whether CRP concentration can be used as a marker for relapse in dogs with multicentric lymphoma. DESIGN: Cohort study. ANIMALS: 20 dogs with multicentric lymphoma and 8 healthy control dogs undergoing chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP) or with vincristine, cyclophosphamide, methotrexate, and L-asparaginase (VCMA) and 20 other healthy dogs. PROCEDURES: Serum CRP concentration was measured weekly during the first month of chemotherapy and then at 3-week intervals until relapse in dogs with multicentric lymphoma, weekly for 16 weeks in healthy dogs undergoing chemotherapy, and once in the healthy dogs not undergoing chemotherapy. RESULTS: For both groups of dogs with lymphoma, mean serum CRP concentration during week 1 (prior to treatment) was significantly higher than mean concentrations following induction of chemotherapy and at the time of relapse. Mean serum CRP concentration in the healthy dogs undergoing chemotherapy was not significantly different at any time from mean concentration for the healthy dogs not undergoing chemotherapy. No significant differences were observed between dogs treated with CVP and dogs treated with VCMA. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that serum CRP concentration is high in dogs with multicentric lymphoma but that serum CRP concentration is not a useful marker for relapse and that chemotherapy itself does not affect serum CRP concentration.     

Treatment of canine lymphoma with COPLA/LVP

Seventy-five dogs with cytopathologically or histopathologically confirmed lymphoma received L-asparaginase, vincristine, cyclophosphamide, prednisone, and doxorubicin (COPLA) induction followed by chlorambucil, vincristine, and prednisone (LVP) maintenance between January 1994 and June 1997. Toxicity was evaluated using the National Cancer Institute (NCI) toxicity criteria. Age, weight, sex, and response were evaluated for prognostic significance against first remission duration. A complete response (CR) was obtained in 61 (80%) dogs, a partial response (PR) was obtained in nine (12%) dogs, and no response (NR) was obtained in five (8%) dogs. The median first remission duration was 25 weeks, with 17% and 5% of the dogs in remission at one and two years, respectively. Observed toxicity was low, with 84% of dogs given an NCI score of 1 or 2. Median survival time for dogs achieving CR was 36 weeks versus four weeks for those achieving PR or NR.     

Neutropenia associated with vincristine and L-asparaginase induction chemotherapy for canine lymphoma

Vincristine (VCR) and L-asparaginase (L-ASP) are commonly used to treat canine lymphoma. As single agents, these drugs are not myelosuppressive. However, in combination, VCR and L-ASP cause severe neutropenia in some dogs. It has been recommended that L-ASP be administered 12-24 hours after VCR to minimize toxicity. The purpose of this retrospective study was to determine the prevalence of neutropenia after VCR/L-ASP induction therapy for canine lymphoma and to evaluate risk factors for myelosuppression, especially the interval between VCR and L-ASP administration. Medical records of 147 dogs were reviewed. L-ASP was given 0 (n = 50), 6 (n = 23), 18 (n = 20), or 24 (n = 54) hours after VCR. Forty percent of the dogs were neutropenic 7 days after VCR/L-ASP, and 18% had neutrophil counts of <1,000 cells/microL. The median neutrophil count was 3,712 cells/microL (range 0-30,968 cells/microL). No correlation was found between administration interval and day 7 neutrophil count (P = .84) or development of gastrointestinal signs, including vomiting (P = .80), diarrhea (P = .52), and decreased appetite (P = .30). No significant predictors of neutropenia were identified. Higher clinical stage and substage b were associated with decreased appetite after treatment (P = .04 and .01, respectively). Sixteen percent of the dogs were hospitalized. This study demonstrates that VCR/L-ASP induction for canine lymphoma may result in neutropenia but that separation of VCR and L-ASP administration may not be necessary to avoid toxicity.     

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.     

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.     

Preclinical evaluation of L-asparaginase and methotrexate administered at intermediate doses in dogs.

The role of L-asparaginase (L-ASP) in limiting signs of methotrexate (MTX) toxicosis was studied. Eight dogs were randomly allotted to 2 groups of 4 dogs. All dogs were given 400 IU of L-ASP/kg of body weight IM, on day 1. On day 10, group-1 dogs were given 3 mg of MTX/kg, IV, and group-2 dogs were given 6 mg of MTX/kg, IV. All dogs were given 400 IU of L-ASP/kg, IM, 24 hours later (on day 11). One group-2 dog was euthanatized on day 16 because of severe gastrointestinal signs that were unresponsive to treatment. A second dose of MTX, identical to that given on day 10, was given on day 20 to each surviving dog, followed by L-ASP on day 21. On day 67, the 7 surviving dogs were given 3 mg of MTX/kg, IV. Adverse reactions observed were vomiting, diarrhea, and weight loss. Gastrointestinal side effects of MTX were not attenuated with L-ASP and would be a serious limitation to use of MTX administered at an intermediate dose in the treatment of lymphoma in dogs.     

Effects of L-asparaginase on plasma amino acid profiles and tumor burden in cats with lymphoma

BACKGROUND: L-Asparaginase (Elspar(a)), is an Escherichia coli-derived enzyme that depletes lymphoma cells of asparagine, inhibiting protein synthesis and resulting in cell death. The single agent response rate in cats with lymphoma and impact of L-asparaginase on plasma amino acid concentrations is unknown. HYPOTHESES: L-Asparaginase significantly reduces plasma asparagine concentrations and has demonstrable efficacy against untreated lymphoma in cats. ANIMALS: Thirteen cats with confirmed lymphoma (LSA) of any anatomic site were given 1 dose 400 IU/kg IM) of L-asparaginase for initial LSA treatment. METHODS: Plasma collected at 0, 2, and 7 days after L-asparaginase therapy was assayed for ammonia, asparagine, aspartic acid, glutamine, and glutamic acid concentrations. Cats were restaged 7 days later to assess tumor response. Results: Eight cats had T-cell LSA, 4 cats had B-cell LSA, and 1 cat's immunophenotype was unknown. Two complete and 2 partial responses to L-asparaginase were seen. Four cats had stable disease, and 5 cats had progressive disease. Ammonia and aspartic acid concentrations were increased from baseline at 2 and 7 days posttreatment. Asparagine concentrations were decreased from baseline at 2 days but not 7 days posttreatment. Glutamic acid concentrations were increased at day 2 compared to day 7 posttreatment but not compared to baseline. Glutamine concentrations were unchanged. CONCLUSIONS AND CLINICAL IMPORTANCE: L-asparaginase significantly reduced asparagine concentrations within 2 days of treatment, but this effect was lost within 7 days. The apparent overall response rate of feline LSA to L-asparaginase in this study was 30%.     

Minimal residual disease in lymph nodes after achievement of complete remission predicts time to relapse in dogs with large B‐cell lymphoma

Most dogs with large B‐cell lymphoma (LBCL) that undergo chemotherapy and achieve clinical complete remission (CR) eventually relapse. However, time to relapse (TTR) is unpredictable. The aims of this prospective study were to assess the influence of post‐chemotherapy lymph node (LN) infiltration by large CD21+ cells using flow cytometry (FC) on TTR, and to establish a cut‐off value of prognostic significance. Dogs with newly‐diagnosed, completely staged LBCL in CR after treatment were enrolled. Minimal residual disease (MRD) analysis by FC was performed on LN aspirates. TTR was calculated between MRD and relapse. Thirty‐one dogs were enrolled: 4% had stage V disease, and diffuse large B‐cell lymphoma was the most common histotype (74%). Based on LN infiltration at MRD evaluation, three groups were created: (a) acellular samples, (b) ≤0.5% infiltration and (c) >0.5% infiltration. Overall median TTR was 154 days (range, 31‐1974): 22 (71%) dogs relapsed during the study period, whereas 9 (29%) dogs did not. The difference among the three groups was significant (P = 0.042 log‐rank test): median TTR was not reached for dogs with LN infiltration ≤0.5% (range, 195‐429 days), 164 days (range 63‐1974) for dogs with acellular LN samples, and 118 days (range, 31‐232) for dogs with LN infiltration >0.5%. These results demonstrate that MRD assessment by FC on LN aspirates in dogs with LBCL in clinical CR predicts TTR. LN infiltration by >0.5% large CD21+ cells after treatment is an unfavourable prognostic factor.     

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.     

Monitoring of Minimal Residual Disease (MRD) after Multidrug Chemotherapy and Its Correlation to Outcome in Dogs with Lymphoma: A Proof‐of‐Concept Pilot Study

Background: Tumor cell burden in dogs with lymphoma cannot be assessed accurately by diagnostic evaluation during clinical complete remission (CR). Recent advances in polymerase chain reaction (PCR)‐based methods enabled us to quantify minimal residual disease (MRD) in canine lymphoma. Hypothesis/Objectives: To quantify MRD in dogs with lymphoma treated with multidrug chemotherapy and to correlate it with remission duration after chemotherapy. Animals: Seventeen dogs with lymphoma that achieved CR by multidrug chemotherapy. Methods: Rearranged immunoglobulin heavy chain or T‐cell receptor γ chain gene fragments from lymphoma cells were PCR amplified and sequenced to prepare clone‐specific primers and probes for real‐time PCR to quantify MRD. MRD in the peripheral blood was monitored during and at the end of a 25‐week multidrug chemotherapy protocol. Correlation between MRD at the end of chemotherapy and remission duration after chemotherapy was analyzed. Results: MRD gradually decreased after initiation of multidrug chemotherapy, reached a nadir as low as <0.019–1.0 cells/μL at weeks 4–17, and remained low or slightly increased until week 25. MRD at the end of chemotherapy was negatively correlated with remission duration from the end of chemotherapy to relapse. Conclusion and Clinical Importance: MRD could be an objective marker to indicate tumor cell burden in dogs with lymphoma even in clinical CR. MRD at the end of chemotherapy could be a prognostic factor to predict remission duration after chemotherapy.     

A combination chemotherapy protocol with MOPP and CCNU consolidation (Tufts VELCAP-SC) for the treatment of canine lymphoma

A chemotherapy protocol using a consolidation phase of alkylating agents was used for treating 94 dogs with lymphoma. Fifty‐seven percent of dogs were in stage V, 63% were ill and 38% had T‐cell lymphoma. The complete remission (CR) rate was 70% and is comparable to results achieved with previously published chemotherapy protocols. Anorexia predicted the remission; of the 40 dogs without anorexia, 35 (88%) achieved CR whereas of 52 dogs with anorexia, 30 (58%) achieved CR. Median first CR duration was 168 days and 1‐ and 2‐year CR rates were 17.4 and 15.5%, respectively. Platelet count affected length of first CR, with a 53.2% reduced chance of coming out of remission with each log increase in platelet count. Median survival time was 302 days. One and 2‐year survival rates were 44 and 13%, respectively. Anorexia and no dose reduction of any drug were independent negative variables. Of 93 dogs with toxicity data, 65 dogs (70%) required a dose reduction. Cyclophosphamide was most commonly reduced with reductions in 31 (38%) of 82 dogs. A dose reduction was significantly more likely in dogs with B‐cell lymphoma than in those with T‐cell lymphoma.     

Prognostic value of baseline absolute lymphocyte concentration and neutrophil/lymphocyte ratio in dogs with newly diagnosed multi‐centric lymphoma

Canine multi‐centric B‐cell lymphoma shares similarities with diffuse large B‐cell (Non‐Hodgkin's) lymphoma (NHL) in people. In people with NHL, lymphopenia at diagnosis and first relapse and neutrophil/lymphocyte ratio (N:L) > 3.5 are negative prognostic factors for survival. The objective of this study was to determine if lymphocyte concentration at diagnosis and first relapse and N:L were prognostic for survival in dogs with newly diagnosed multi‐centric lymphoma. Medical records of 77 dogs with multi‐centric lymphoma treated with a CHOP‐based chemotherapy protocol were retrospectively evaluated. Absolute lymphocyte concentration and N:L ratio at presentation of dogs pre‐treated with steroids was not significantly different from dogs who had not received steroids. On multivariate analysis, only immunophenotype remained significant for progression‐free survival (PFS), whereas no variables remained significant for ST. A prospective study of these haematologic variables is warranted to assess their true significance.     

Evaluation of an actinomycin-D-containing combination chemotherapy protocol with extended maintenance therapy for canine lymphoma

In this retrospective study, a 6-drug (prednisone, L-asparaginase, vincristine, cyclophosphamide, doxorubicin, and actinomycin-D) chemotherapy protocol with extended maintenance for the treatment of lymphoma was evaluated for efficacy and toxicity in 39 dogs. The complete remission rate was 97%, with a median progression-free survival (PFS) of 331 d. The median overall survival (OS) was 461 d. Of the variables evaluated for prognostic significance, only immunophenotype and sex were found to be prognostic. Dogs with T-cell lymphoma had shorter PFS and OS than dogs with B-cell lymphoma. Castrated male dogs had a shorter PFS and OS than spayed female dogs. Although the majority of dogs experienced one or more episodes of chemotherapy associated toxicity, the majority of these episodes were mild and self-limiting. The results of this study warrant further investigation into the value of extended maintenance therapy and inclusion of actinomycin-D in combination chemotherapy protocols for canine lymphoma.