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).     

Oral melphalan for the treatment of relapsed canine lymphoma

Oral melphalan has been included in multi‐agent rescue protocols for canine lymphoma but its activity as a single‐agent for this purpose has not been established. Inexpensive cost, ease of administration and tolerability make oral melphalan an attractive candidate for single‐agent rescue therapy of canine lymphoma. Retrospective evaluation of 19 cases of relapsed canine lymphoma treated with oral melphalan was performed. Melphalan was primarily administered (n = 16) via a high dose protocol (HDM ) with a median dosage of 19.4 mg m^?2. Fifteen dogs (78.9%) were treated concurrently with corticosteroids. Response evaluation was possible for all dogs with a calculated overall clinical benefit (partial response [PR ] + stable disease [SD ]) of 31.6% (PR 3/19; SD 3/19). Times to progression following melphalan (TTP ‐M) were 14, 24 and 34 days for responders and 20, 28 and 103 days for dogs experiencing SD . Twelve of 17 dogs evaluable for toxicity experienced an adverse event (AE ) with only 3 dogs experiencing a grade III or higher AE . Haematologic toxicity was common (11/17) while gastrointestinal toxicity was rare (1/17). Although treatment resulted in limited clinical benefit and non‐durable responses, oral melphalan was well‐tolerated and may be a reasonable rescue option in cases where minimal effective agents remain.     

Epirubicin as part of a multi‐agent chemotherapy protocol for canine lymphoma

The aim of the study was to report the outcome of treatment of 97 dogs with lymphoma that received a multi‐agent chemotherapy protocol containing epirubicin as the primary anthracycline. Seventy‐five dogs received a 25‐week protocol with no maintenance phase whilst 22 dogs received a maintenance phase. Complete response rate was 96% and time to first relapse (TTR) and overall survival (OS) time for all dogs were 216 and 342 days, respectively. Dogs with T‐cell lymphoma and those classified as WHO substage b had significantly poorer OS times and TTR. The protocol was well tolerated with toxicity similar to doxorubicin‐containing protocols. Epirubicin as part of a multi‐agent protocol is safe and effective in the treatment of canine multicentric lymphoma. There is a high initial response rate and an overall median survival time that is similar to other published doxorubicin‐containing protocols.     

A dexamethasone,melphalan, actinomycin‐D and cytarabine chemotherapy protocol as a rescue treatment for feline lymphoma

Nineteen cats with relapsed high‐grade/large‐cell lymphoma were treated with dexamethasone, melphalan, actinomycin‐D and cytarabine (DMAC). All cats had received Cyclophosphamide, Vincristine, Prednisolone (COP) as first‐line chemotherapy and most cats had received at least 2 prior rescue agents with 14 of 19 having received both epirubicin and lomustine. Five cats (26%) exhibited a response (defined as an improvement or resolution of tumour‐associated clinical signs/tumour volume, or complete/partial response) to chemotherapy though no patients received more than 2 cycles of DMAC. Most cats tolerated the protocol well though 3 patients exhibited Veterinary Cooperative Oncology Group (VCOG) grade 4 neutropenia and 1 patient exhibited grade 4 thrombocytopenia. The median progression‐free survival and overall survival from starting DMAC were 14 and 17 days respectively. There is still an unmet need for successful rescue chemotherapy protocol for cats with relapsed lymphoma. [Correction added on 02 November 2017, after first online publication: The expansion for the term DMAC was previously incorrect and has been corrected in this current version.]     

Thymidine kinase assay in canine lymphoma

The aim of the study was to evaluate if thymidine kinase (TK) correlated with duration of first remission (DFR) or survival in dogs with lymphoma and if initial TK levels correlated with stage and substage; and also to assess if TK level at diagnosis correlated with immunophenotype. TK was assayed in 73 dogs with treatment naïve lymphoma, then again after treatment; 47% had an initial TK above the reference interval. Dogs with B‐cell lymphoma had higher initial TK activities than dogs with T‐cell lymphoma. TK levels were not higher in dogs with higher stage disease and TK activity prior to treatment was not associated with DFR or survival. Where TK was elevated at diagnosis, it fell into the reference range during remission. TK was normal in 53% dogs at diagnosis, which is higher than previously reported. Further studies are warranted to assess the utility of TK in dogs with lymphoma.     

Efficacy and toxicity of BOPP and LOPP chemotherapy for the treatment of relapsed canine lymphoma*

Mechlorethamine (Mustargen^®, Oncovin^® (vincristine), procarbazine and prednisone (MOPP) chemotherapy is useful for relapsed canine lymphoma. This study evaluates the efficacy of MOPP after substitution of CCNU (lomustine, LOPP protocol) or BCNU (carmustine, BOPP protocol) for mechlorethamine in 60 dogs with relapsed lymphoma. Seven of 14 (50%) dogs treated with BOPP responded, for a median of 129.5 days for complete responders (range 9–354 days) and a median of 140 days for partial responders (range 4–276 days). Twenty‐three of 44 (52%) dogs treated with LOPP responded for a median of 112 days for complete responders (range 48–250 days) and a median of 84.5 days for partial responders (range 69–290 days). Two dogs receiving a combination of LOPP and BOPP partially responded for 28 and 163 days, respectively. With BOPP chemotherapy, nine dogs (20.5%) and seven dogs (50%) had one or more episodes of Grade II or higher neutropenia and thrombocytopenia, respectively. Seven dogs (50%) had one or more episodes of Grade II or higher gastrointestinal toxicity. While receiving LOPP chemotherapy, 28 dogs (63.6%) and 17 dogs (38.6%) had one or more episodes of Grade II or higher neutropenia and thrombocytopenia, respectively. Seventeen dogs (38.6%) had one or more episodes of Grade II or higher gastrointestinal toxicity. Overall, there were 17 non‐fatal treatment‐related episodes of sepsis requiring hospitalization. Eight dogs (13%) died or were euthanized because of treatment‐related sepsis and/or chemotherapy‐related complications. Severe haematologic toxicity, coupled with the improved response duration observed in dogs receiving reduced doses during B/L‐OPP rescue, underscores the need for protocol optimization.     

Efficacy and toxicity of carboplatin and cytarabine chemotherapy for dogs with relapsed or refractory lymphoma (2000–2013)

Medical records of 22 dogs treated with carboplatin (n = 8) or carboplatin and cytarabine (n = 14) chemotherapy for relapsed or refractory lymphoma between 2000 and 2013 were retrospectively reviewed. The clinical response rate was 18.2% (4/22). Median time to progression was 18 days (56 for responders; 12 for non‐responders, P = 0.0006). Median overall survival time was 28 days (109 for responders; 21 for non‐responders, P = 0.0007). Thrombocytopenia and neutropenia occurred in 84.2% (16/19) and 52.6% (10/19), respectively. Grade IV thrombocytopenia and neutropenia occurred in 56.3% (9/16) and 60.0% (6/10), respectively. Dogs that received both drugs were more likely to become neutropenic (P = 0.022) or thrombocytopenic (P = 0.001) than dogs receiving carboplatin alone. All responders received both drugs giving a 28.6% (4/14) response rate for the combination. Although some dogs responded to the combination, toxicity was high and the responses were not durable. With adequate supportive care, this protocol may be an acceptable rescue option for some dogs.     

Pilot clinical study of carmustine associated with a lipid nanoemulsion in combination with vincristine and prednisone for the treatment of canine lymphoma

A lipid nanoemulsion (LDE) resembling low‐density lipoprotein can target malignant tumours. In in vivo and clinical studies, association of chemotherapeutic agents to LDE decreased their toxicity and increased pharmacological action. Here, safety of LDE as carmustine carrier (50 mg m^?2, intravenous) combined with vincristine and prednisone for the treatment of dogs with lymphoma was tested and compared with commercial carmustine with vincristine and prednisone. In five dogs from LDE‐carmustine and six from commercial carmustine, complete remission was achieved (P > 0.05). Partial remission occurred in two dogs from each group. In both groups, the median progression‐free intervals (119 and 199 days) and overall survival times (207 and 247 days) were equal. Neutropenia was observed in both groups, but no other major toxicities occurred. Therefore, no difference was observed between the treatments. LDE‐carmustine was shown to be safe and effective in a drug combination protocol, which encourages larger studies to investigate the use of this novel formulation to treat canine lymphomas.     

Evaluation of treatment with doxorubicin and piroxicam or doxorubicin alone for multicentric lymphoma in dogs

OBJECTIVE: To evaluate the antitumor and toxic effects of treatment with doxorubicin combined with piroxicam or doxorubicin alone for multicentric lymphoma in dogs. DESIGN: Nonrandomized clinical trial. ANIMALS: 75 dogs with multicentric lymphoma. PROCEDURE: 33 dogs were treated with doxorubicin (30 mg/m2, IV, q 21 d, for 3 doses) and piroxicam (0.3 mg/kg [0.14 mg/lb], PO, q 24 h); results were compared with a historical control group of 42 dogs treated with doxorubicin (30 mg/M2, IV, q 21 d, for 3 doses) alone. Results-The percentages of dogs that had remission with doxorubicin-piroxicam treatment (79%) or doxorubicin treatment alone (74%) were not significantly different. Median duration of first remission was 130 days with doxorubicin-piroxicam and 147 days with doxorubicin alone; these values were not significantly different. Severe toxicosis was observed in 22% of dogs treated with doxorubicin-piroxicam and 17% of dogs treated with doxorubicin alone. CONCLUSIONS AND CLINICAL RELEVANCE: Both treatment protocols were efficacious and well tolerated. The doxorubicin-piroxicam treatment was no more effective regarding response rate, remission duration, or survival duration, compared with the control group treated with doxorubicin alone.     

Fractionated oral dosing and its effect on cyclophosphamide pharmacokinetics in dogs with high-grade multicentric lymphoma

Cyclophosphamide (CP) is an alkylating agent commonly included in multi-drug treatment protocols for canine cancer. As a prodrug, CP requires hepatic metabolism for activation to the intermediate compound 4-hydroxycyclophosphamide (4-OHCP) which then spontaneously forms alkylating phosphoramide mustard. CP is frequently administered in a fractionated manner, with the total dose given over multiple days. CP is reported to cause auto-induction of metabolism in humans, with faster CP clearance and relatively increased 4-OHCP formation following fractionated versus bolus dosing, however canine pharmacokinetic studies of CP dose fractionation are lacking. The study objective was to evaluate the pharmacokinetics of fractionated oral CP dosing at a dose of 200–250 mg/m² over 3 to 4 days in a prospectively identified population of cancer-bearing dogs. Plasma concentrations of CP and 4-OHCP were measured by ultra-high performance liquid chromatography tandem-mass spectrometry in eight dogs following the first and last doses to assess for auto-induction of CP metabolism. No significant difference in the rate of CP elimination between first and last doses were detected (0.73 ± 0.46 vs. 1.22 ± 0.5 h⁻¹; p = .125). Additionally, no significant difference in dose-normalized 4-OHCP exposure was identified between first and last doses (5.9 ± 2.1 vs. 7.9 ± 6.4 h × ng/ml; p = .936). These results suggest that fractionated dosing may not increase exposure to the active metabolite of CP in dogs as it does in humans. As such, standard bolus dosing and fractionated dosing may be equivalent in terms of bio-activation of CP in dogs administered a dose of 200–250 mg/m².     

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.     

Mechlorethamine,vincristine, melphalan and prednisone (MOMP) for the treatment of relapsed lymphoma in dogs

Eighty‐eight dogs with relapsed lymphoma were treated with the MOMP (mechlorethamine, vincristine, melphalan and prednisone) protocol on a 28‐day treatment cycle. The overall response rate (ORR) to the MOMP protocol was 51.1% for a median of 56 days (range 7–858 days). Twelve percent of dogs experienced a complete response for a median of 81 days (range 42–274 days) and 38.6% experienced a partial response for a median of 49 days (range 7–858 days). Dogs with T‐cell lymphoma had an ORR of 55% for a median of 60 days (range 49–858 days) while those with B‐cell lymphoma had an ORR of 57% for a median of 81 days (range 7–274 days) (P = 0.783). The overall survival time for all dogs was 183 days (range 17–974 days). Fifty‐four percent of dogs experienced toxicity with the majority classified as grade I. The MOMP protocol seems well‐tolerated and is an option for dogs with relapsed lymphoma.     

Evaluation of mechlorethamine,vinblastine, procarbazine,and prednisone for the treatment of resistant multicentric canine lymphoma

Multi-agent chemotherapy successfully induces remission in most naïve, high-grade canine lymphoma patients; however, disease recurrence is common. MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) is an effective rescue protocol used to re-induce remission, but is associated with gastrointestinal toxicity and can be a less desirable option for patients that previously failed vincristine-containing protocols. Therefore, alternative members of the vinca alkaloid family, such as vinblastine, could be potentially advantageous as substitutes for vincristine to reduce gastrointestinal toxicity and chemoresistance. The objective of this study was to report the clinical outcomes and toxicity of 36 dogs with relapsed or refractory multicentric lymphoma treated with a modified MOPP protocol whereby vincristine was replaced with vinblastine (MVPP). The overall response rate to MVPP was 25% with a median progression free survival of 15 days and a median overall survival of 45 days. MVPP at the prescribed doses resulted in modest and transient clinical benefit, but was well tolerated with no treatment delays or hospitalizations secondary to side effects. Given the minimal toxicity, dose intensification could be considered to improve clinical responses.     

Serial haemostatic monitoring of dogs with multicentric lymphoma

Lymphoma is the most common haematopoietic malignancy in dogs and it has been associated with hypercoagulability and subsequent thromboembolism. The objectives of this study were to serially characterize the haemostatic status of dogs with multicentric lymphoma. Thromboelastography, thrombin–antithrombin complex concentration and routine haematology and coagulation panels were measured. Twenty‐seven dogs were included in the study and 15 completed the study in remission. At presentation, 81% (22/27) of dogs with multicentric lymphoma had altered haemostatic profiles consistent with hypercoagulability. Laboratory evidence of hypercoagulability did not resolve during treatment or for up to 1 month following attainment of clinical remission. Accelerated rate of clot formation at the time of chemotherapeutic protocol completion was associated with decreased survival time. We concluded that dogs with multicentric lymphoma were frequently hypercoagulable from presentation through 4 weeks after the completion of chemotherapy. Increased angle and shortened K in dogs that have successfully completed their chemotherapeutic protocol may be associated with shorter survival times.     

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.     

Safety evaluation of combination doxorubicin and toceranib phosphate (Palladia®) in tumour bearing dogs: a phase I dose‐finding study

Combination chemotherapy holds promise for improving outcomes in malignancy when compared with single‐agent approaches. Care must be taken to avoid overlapping toxicity and to utilize agents with differing mechanisms of action. A phase I dose‐finding trial was performed to determine the maximally tolerated dose (MTD) of a concurrent toceranib and doxorubicin (DOX) combination protocol where toceranib dose was maintained at or near 2.75 mg kg^?1 by mouth every other day (PO EOD) while escalating DOX dosage. The dose‐limiting toxicity was found to be neutropenia and the MTD of the combination was determined to be 25 mg m^?2 of DOX q 21 days given concurrently with toceranib 2.75 mg kg^?1 PO EOD. This combination was well tolerated with no excessive gastrointestinal toxicity nor novel adverse events (AEs) noted. Anti‐tumour activity was observed in the majority of cases. This combination warrants further investigation in the context of phase II/III clinical trials to characterize efficacy and long‐term AE profiles.     

A preliminary assessment of whole-body radiotherapy interposed within a chemotherapy protocol for canine lymphoma

Six dogs with spontaneously occurring, previously untreated lymphoma were treated with half‐body radiation therapy (RT) doses interposed in a CHOP‐based 25‐week chemotherapy regimen. Chemotherapy‐related toxicities were as expected and were mildly increased in severity post‐RT compared with pre‐RT. Treatment was delayed by 1–2 weeks per delay in four dogs due to chemotherapy‐related neutropenia. Radiation therapy was administered in two consecutive day fractions of 4 Gray to the cranial and caudal halves of the body 4 weeks apart. Radiation‐related toxicities consisted of lethargy, alopecia, diarrhoea of less than 2‐day duration and average decreases in neutrophil counts of 50%. Late effects from RT were not evident. Median remission and survival times for the six dogs were 455 and 560 days, respectively. The protocol was well tolerated and should be studied further to evaluate the potential therapeutic gain of the addition of RT to chemotherapy for the treatment of canine lymphoma.     

Efficacy of doxorubicin as an induction agent for cats with lymphosarcoma

OBJECTIVE: To determine the efficacy of doxorubicin when used alone in inducing remission in cats with lymphosarcoma. DESIGN: Prospective multi-institutional study of naturally occurring disease. METHODS: Cases were accrued from veterinary institutions in Australia and New Zealand after obtaining consent from informed owners. Cats were treated with doxorubicin every 3 weeks for three treatments. If there was no response to the first dose of doxorubicin or if the cat relapsed during the doxorubicin regimen, the cat was withdrawn from the trial and either euthanased or treated with other agents. Age, breed, gender and anatomic site of the lymphosarcoma (multicentric, alimentary, mediastinal, extranodal) were recorded for each cat. Clinical remission was assessed before each treatment by physical examination, radiography, ultrasonography and computed tomography where appropriate. Complete remission was defined as the disappearance of all clinical signs and clinically detectable tumour. RESULTS: Twenty-one cases were accrued over a 2-year-period but only 19 were available for data analysis. Young Siamese cats were over-represented and all cats with mediastinal tumours were young Siamese. There was a significant difference between the mean ages of cats with mediastinal or multicentric lymphosarcoma (mean +/- SD: 3.5 +/- 3.0 and 4.3 +/- 2.6 years, respectively) and cats with alimentary or extranodal LSA (11.4 +/- 0.9 and 11.0 +/- 0.9 years, respectively). Of 19 cats treated with doxorubicin alone, 6 (32%) had complete remission, 6 (32%) had partial remission and 7 (36%) did not respond. CONCLUSIONS: The results suggest that doxorubicin cannot be recommended as a single agent for treatment of feline lymphosarcoma because of the rather poor remission rate achieved.     

Long-term survival after combination chemotherapy for bilateral renal malignant lymphoma in a dog

CASE HISTORY: A 6-year-old, entire male Flat-coated Retriever was presented with a history of lethargy, polydipsia and seizures. Clinical chemistry had shown marked azotaemia.

CLINICAL FINDINGS AND DIAGNOSIS: Radiography and ultrasonography revealed bilateral renomegaly, and cytology of fine needle aspirates from the kidneys was diagnostic of malignant lymphoma. The dog was treated with a modified high-dose cyclophosphamide-, vincristine-, and prednisolone-based chemotherapy protocol, achieved remission, and returned to normal quality of life. Survival time was 346 days from the time of diagnosis.

CLINICAL RELEVANCE: Malignant lymphoma in the kidneys of dogs has been considered to carry a uniformly poor prognosis. Long-term remission after medical treatment has not previously been reported. The favourable outcome in this case illustrates the limitations of clinical staging in determining the outcome for individual patients.     

Evaluation of a multi‐agent chemotherapy protocol combining dexamethasone,melphalan, actinomycin D,and cytarabine for the treatment of resistant canine non‐Hodgkin high‐grade lymphomas: a single centre's experience

The DMAC protocol (dexamethasone, melphalan, actinomycin‐D, cytarabine) has been evaluated in American studies for the treatment of relapsed canine lymphoma, comparing similarly to other rescue protocols. The aim of this study was to evaluate efficacy and toxicity of DMAC, in a larger UK cohort of resistant canine lymphomas. Medical records of dogs with resistant non‐Hodgkin high‐grade lymphomas that received DMAC as a rescue protocol were reviewed from 2007 to 2017. Response, time from initiation to discontinuation (TTD) and toxicity (Veterinary Cooperative Oncology Group criteria) were assessed. One hundred dogs were included; 86 received CEOP (modified CHOP including epirubicin) as first‐line treatment. Thirty‐five dogs (35%) responded: 21 complete responders (CRs) and 14 partial responders (PRs). Responders had significantly longer TTD (P < 0.001) compared with non‐responders: 62 days (range 28‐952) for CR vs 32 days (range 20‐70) for PR. Six CR received more than six cycles of DMAC (range 7‐36 cycles) and experienced a longer TTD (median 508, range 126‐952 days). Thrombocytopenia occurred in 45% (24 grade 1‐2, 21 grade 3‐4) and neutropenia in 36% of cases (29 grade 1‐2, 7 grade 3‐4). Gastrointestinal toxicity occurred in 42% of dogs (40 grade 1‐2, 2 grade 3‐4). Owing to chemotherapy toxicity, treatment was discontinued in five, and hospitalization required in six cases. In this study, response to DMAC was lower and of generally shorter duration than previously reported. Toxicity was high, but infrequently led to hospitalization or discontinuation of treatment.