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.     

Prognostic significance of CD25 expression in dogs with a noninvasive diagnosis of B-cell lymphoma treated with CHOP chemotherapy

Prior studies have identified high CD25 expression in canine diffuse large B-cell lymphoma as a negative prognostic indicator. The objective of this retrospective study was to evaluate CD25 expression as a prognostic indicator in dogs with B-cell lymphoma (BCL) diagnosed with commonly used noninvasive diagnostics (cytology and flow cytometry [FC]) and treated with CHOP chemotherapy. Lymph node aspirates from 57 dogs with cytologic diagnosis of lymphoma composed of intermediate to large lymphocytes were analysed with FC. Percentage of neoplastic B-cells expressing CD25 and median fluorescence intensity (MFI) of CD25 were measured. Relationships of CD25 percent positivity and MFI to progression free survival (PFS) and survival time were evaluated. Median survival time (MST) of all dogs was 272 days (95% CI, 196–348 days) and median PFS was 196 days (95% CI, 172–220 days). Higher percentage of B-cells positive for CD25 was associated with decreased risk of death in multivariable analysis (p = .02). Dogs with higher CD25 positivity had longer MST and PFS than dogs with lower CD25 positivity (318 days versus 176 days and 212 days versus 148 days, respectively), but these differences were not significant. CD25 MFI was not significantly associated with outcome. Based on the results of this study, the association of CD25 expression and prognosis in dogs with BCL diagnosed using noninvasive methods should be interpreted with caution. Further evaluation, with studies that include histopathologic differentiation of lymphoma subtypes, is needed.     

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.     

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.     

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.     

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.     

Clinical presentation,treatment and outcome in 31 dogs with presumed primary colorectal lymphoma (2001–2013)

The objective of this multicentre retrospective study was to describe clinical presentation, treatment and outcome and to determine prognostic factors for dogs with presumed primary colorectal lymphoma (PCRL). A total of 31 dogs were included. The predominant features of PCRL were high grade (n = 18) and immunophenotype B (n = 24). Most dogs were substage b (n = 25) with higher prevalence of haematochezia (n = 20). One dog had surgery only. Thirty dogs received chemotherapy; amongst them 13 had surgery or radiotherapy. Progression free survival (PFS) was 1318 days and disease‐related median survival time (MST) was 1845 days. Fourteen dogs were alive at the end of the study with a median follow‐up time of 684 days (3–4678 days). Younger dogs had longer PFS (P = 0.031) and disease‐related MST (P = 0.01). Presence of haematochezia corresponded with longer PFS (P = 0.02). Addition of local treatment to chemotherapy did not significantly improve the outcome (P = 0.584). Canine PCRL has considerably longer PFS and MST than other forms of non‐Hodgkin's lymphoma.     

Positive association between a glutathione‐S‐transferase polymorphism and lymphoma in dogs

Glutathione‐S‐transferase enzymes (GSTs) play an important role in the detoxification of environmental carcinogens. Defective GST genotypes are over‐represented in human cancers; in particular, low activity GSTT1 genotypes are risk factors for non‐Hodgkin lymphoma. We hypothesized that defective GSTT1 genotypes would be associated with lymphoma risk in dogs. To address this, we resequenced the exons, splice junctions, and 3′‐UTR of canine GSTT1 in dogs with lymphoma (n = 93) and age‐matched unaffected dogs (n = 86). Of 27 canine GSTT1 variants identified, the I2+28 G>A was significantly associated with lymphoma [odds ratio (OR) 6.26, 95% confidence interval (CI), 1.77–22.2], with the AA genotype found in 18.3% of affected dogs but only 3.5% of controls (P = 0.002). This intronic variant was predicted to perturb GSTT1 mRNA splicing, and may increase lymphoma risk by impairing detoxification of environmental chemicals. Confirmation of this finding in a larger population of dogs may support the inclusion of GSTT1 genotyping in epidemiologic studies of canine lymphoma risk.     

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 the modified Glasgow Prognostic Score to predict outcome in dogs with newly diagnosed lymphoma

The modified Glasgow Prognostic Score (mGPS) assigns a numerical value (0–2) from pre‐treatment serum concentrations of C‐reactive protein (CRP) and albumin to predict patient outcome. CRP and albumin were evaluated in 77 untreated dogs with lymphoma to determine the relationship of mGPS to clinicopathological parameters and whether it could predict progression‐free (PFS) and overall survival (OS) in treated dogs. mGPS distribution was significantly associated with clinical stage, substage b, weight loss, gastrointestinal disturbances and lethargy at presentation. On univariate analysis, mGPS was significantly associated with OS and PFS, with shorter median survival times for mGPS 2 compared to mGPS 0 and 1 combined. Hypoalbuminaemia significantly reduced OS and PFS, however increased CRP had no effect. Only clinical stage was significantly associated with OS and PFS on both univariate and multivariate analysis. mGPS has potential prognostic value for canine lymphoma , but further studies are needed.     

Utility of a multiple serum biomarker test to monitor remission status and relapse in dogs with lymphoma undergoing treatment with chemotherapy

A blinded retrospective study was conducted to investigate remission and recurrence of lymphoma in dogs receiving chemotherapy. The objective was to compare clinicians' assessment using palpation and cytology to the results of serum biochemical tests for haptoglobin (Hapt) and C‐reactive protein (C‐RP). These biochemical test results were combined using a diagnostic algorithm developed using data from 344 individual dogs. This multivariate approach, termed the canine lymphoma blood test (cLBT), was used to follow 57 dogs during and after treatment. cLBT of remission and recurrence compared well with clinicians' assessment and differentiated dogs in remission and those with recurring disease before appearance of lymphadenopathy (P < 0.001). The cLBT demonstrated prognostic potential based on pre‐treatment values on dogs with shorter survival times and on those achieving the lowest cLBT score during treatment that showed longer survival times. The test, therefore, demonstrates potential to assist in monitoring treatment of canine lymphoma.     

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.]     

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).     

Temozolomide alone or in combination with doxorubicin as a rescue agent in 37 cases of canine multicentric lymphoma

Temozolomide (TMZ) is an alkylating agent previously used in conjunction with doxorubicin (DOX) to treat dogs with relapsed lymphoma. However, there are very limited data for this drug when used as single agent. The aim of this retrospective study was to evaluate the efficacy and toxicity of TMZ in dogs with relapsed multicentric lymphoma that failed multi‐agent chemotherapy protocols, and compare the outcome to a group of dogs receiving the same drug in combination with DOX. Twenty‐six patients were included in the TMZ group and 11 in the TMZ/DOX group. Responses were evaluated via retrospective review of the medical records. The overall median survival time (MST) for both groups was 40 days (range 1‐527 days). For the TMZ group, median time to progression (TTP) was 15 days (range 1‐202 days) and MST 40 days (range 1‐527 days), with an overall response rate (ORR) of 32% and 46% recorded toxicities. For the TMZ/DOX group, median TTP was 19 days (range 2‐87 days) and MST 24 days (range 3‐91 days), with an ORR of 60% and 63% recorded toxicities. However, a proportion of haematological toxicoses may have gone undetected due to the absence of associated clinical signs. The difference in MST and TTP between the 2 groups was not statistically significant. Similarly, no negative prognostic factors were identified. Although responses were generally short lived, this study suggests that TMZ may achieve similar efficacy to TMZ/DOX whilst being associated with a lower frequency of recorded toxicities.     

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.