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

Abstract

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.

Toxicity of cytarabine constant rate infusion in dogs with high‐grade non‐Hodgkin lymphoma with bone marrow or central nervous system involvement

“…In domestic animals, the main uses are treatment of lymphoproliferative diseases and meningoencephalitis of unknown aetiology . Despite poor efficacy as a single agent in canine lymphoma, cytarabine may have a role to play in CNS (stage V) lymphoma, as it crosses the blood brain barrier .…”

“…15 In domestic animals, the main uses are treatment of lymphoproliferative diseases and meningoencephalitis of unknown aetiology. [17][18][19][20][21][22][23][24] Despite poor efficacy as a single agent in canine lymphoma, 23 cytarabine may have a role to play in CNS (stage V) lymphoma, as it crosses the blood brain barrier. 12,25,26 In addition, cytarabine intensification of induction protocols was associated with increased survival in a small number of patients with bone marrow (BM) infiltration.…”

Lomustine, methotrexate and cytarabine chemotherapy as a rescue treatment for feline lymphoma

“…This route and dose was chosen because it is the predominant choice in previous multi-agent protocols involving cytarabine and is more practical in clinical practice. 13,21,26 Alvarez et al found no significant difference in response between subcutaneous or continuous rate infusion administration as part of the DMAC protocol in dogs (dexamethasone, melphalan, actinomycin D and cytosine arabinoside). 26 However, a pharmacokinetic study of cytarabine in healthy dogs showed that subcutaneous administration, compared with continuous IV administration, limits the ability to maintain steady-state concentrations and overall exposure.…”

“…Methotrexate and cytarabine have been used in multi-agent first-line and rescue protocols in both canine and feline lymphoma, are generally well tolerated and less myelosuppressive than lomustine. 3,13,[20][21][22] Based on these principles, the aim of this retrospective study was to assess the efficacy and tolerability of lomustine, methotrexate and cytarabine chemotherapy as rescue for feline lymphoma.…”

Risk factors associated with the onset of lomustine‐induced neutropenia in tumour‐bearing dogs

“…9,[16][17][18] Prednisone/prednisolone were prescribed at 1-2 mg/kg orally as indicated by the protocol. When CCNU was used as a rescue drug, previous chemotherapy consisted of either high-dose COP, 19 CHOP 20,21 or other rescue agents (e.g., anthracyclines, L-asparaginase, chlorambucil, vinca alkaloids, toceranib phosphate, DMAC protocol [22][23][24] ). Clinical data was collected for treatment of neutropenia/febrile neutropenia, including intravenous fluids, antibiotics, antipyretics and colony-stimulating factor (CSF) agents (e.g., filgrastim) as per the attending clinician's recommendation.…”