Which Drugs Are Used for Medical Management of Lymphoma in Dogs & Cats? Part 3

The following drugs can be used in the management of lymphoma in dogs and cats. Part 3 will discuss dacarbazine, actinomycin D, melphalan, and mitoxantrone.

• Asparaginase
• Doxorubicin
• Vincristine
• Cyclophosphamide
• Lomustine
• Chlorambucil
• Corticosteroids (prednisone and derivatives)
• Cytarabine
• Mechlorethamine
• Procarbazine
• Dacarbazine
• Actinomycin D
• Melphalan
• Mitoxantrone

Dacarbazine, a methylating agent (alkylator) also known as DTIC, is most often used as a single agent or as part of a combination chemotherapy protocol (eg, doxorubicin+DTIC, CCNU [lomustine] +DTIC, temozolomide+DTIC) in the rescue setting for dogs with intermediate- to high-grade lymphoma.^1-7 

Mechanism of action → The exact mechanism underlying the antitumor activity of dacarbazine remains unknown.⁴

• However, it is thought that the active metabolites bind methyl groups to specific DNA sites, which leads to DNA strand breaks, inhibition of DNA synthesis, and subsequent cell death.⁴ 

Dose (dogs only, as single agent) → 800-1000 mg/m² IV as slow infusion over 6 to 8 hours⁵

Dose (dogs only, in combination with CCNU or anthracycline) → 600 mg/m² IV via similar infusion protocol⁷

• Frequency and duration can vary, depending on whether the drug is used as a single agent (q3wk) or as part of a multiagent protocol.^5,6

Monitoring during therapy → Serial CBC evaluations, assessment of hepatic function

Adverse Events

• GI upset, specifically acute emesis during infusion^1,2,4
  • Injectable antiemetics recommended before infusion^1,2,4
• Myelosuppression, particularly thrombocytopenia^1,2,4-6
  • Neutropenia typically occurs 7 to 10 days postadministration.
  • Thrombocytopenia typically occurs between 10 and 21 days postadministration.
• Rare but severe hepatotoxicity reported in humans; unclear whether clinically significant in dogs⁴
• Hypotension can occur if the IV dose is administered rapidly.⁴
• Moderate-to-severe vesicant; extravasation injury can be severe.⁸ 

Key Points

• Dacarbazine is a prodrug that requires bioactivation to active metabolites.⁴ 
• Dose adjustments are indicated in patients with hepatic dysfunction.
• Has not been effectively evaluated in cats
  • Unknown whether cats can metabolize parent drug into active metabolites 

Actinomycin D, also known as dactinomycin, is an antitumor antibiotic of the mitomycin class of chemotherapy agents (ie, derivatives of the soil bacteria of the Streptomyces genus). This drug is most commonly used as a single agent or part of the multiagent rescue DMAC protocol for canine lymphoma.^1,2,9-13 

Mechanism of action → Binds DNA at the transcription initiation complex and prevents RNA chain elongation by RNA polymerase, which leads to inhibition of RNA transcription or protein synthesis and altered cell metabolism^1,10  

Dose (dogs only) → 0.5-0.7 mg/m² IV slowly over 15 to 20 minutes

• Frequency and duration can vary, depending on whether the drug is used as a single agent (q3wk) or incorporated in a multidrug protocol (eg, CHOP, DMAC).^9,11-13

Monitoring during therapy → Serial CBC evaluations 

Adverse Events

• Myelosuppression, including neutropenia 7 to 10 days post-administration and thrombocytopenia ≥14 days postadministration^1,2,10,13 
• GI upset^1,2,10,13
• Tissue damage if perivascular extravasation occurs¹⁰

Key Points

• First antibiotic shown to have anticancer activity¹⁰ 
• Mutation in the multidrug resistance MDR1 gene (also known as ABCB1-1∆) can lead to increased risk for severe side effects.¹⁴
  • Numerous breeds are affected with the MDR1 mutation, including various herding breeds, the silken windhound, and the long-haired whippet.¹⁴
  • Perform MDR1 testing.¹⁵
  • If mutation (heterozygous) is present, major dose reduction is indicated; if patient is homozygous mutant, consider drug omission or substitution.^2,14
• DMAC protocol has not been evaluated in cats, but anecdotal experience suggests it is well-tolerated. 
• Although actinomycin D is less cardiotoxic than doxorubicin, a randomized controlled trial of doxorubicin vs actinomycin D in a multiagent protocol for canine lymphoma documented decreased efficacy of a actinomycin D-based protocol.¹¹
• Another study evaluated actinomycin D as part of maintenance therapy following a standard CHOP protocol for canine lymphoma and documented a higher complete response rate (97%) as compared with historical control studies.¹² 

Melphalan, an alkylating agent of the nitrogen mustard family, is most commonly used to treat canine lymphoma as part of the multiagent DMAC rescue protocol.^1,2,9,16 

Mechanism of action → Binds alkyl groups directly to specific DNA sites, which leads to interstrand and intrastrand cross-links, DNA strand breakage, disruption of DNA synthesis, and subsequent cell death¹⁶

Dose (dogs only, for DMAC protocol) → 20 mg/m² PO on day 7 of a 14-day cycle of the DMAC protocol

Monitoring during therapy → Serial CBC evaluations, assessment of renal function

Adverse Events

• Myelosuppression, particularly thrombocytopenia¹⁶ 
  • Neutrophil nadir typically occurs around 7 to 10 days postadministration.
  • Platelet nadir can occur between 10 and 21 days post-administration.
  • Thrombocytopenia can be cumulative and irreversible because of cytotoxicity against slowly cycling and/or noncycling hematopoietic stem cells.¹⁶ 
• Increased toxicity seen with renal insufficiency^1,16

Key Points

• Active drug that does not require metabolic activation¹⁶

Mitoxantrone is a synthetic anthracenedione compound most commonly used as a rescue agent for intermediate- to high-grade canine lymphoma or as a substitute for doxorubicin in multiagent protocols.^1,2,17-19 

Mechanism of action → Has multiple anticancer mechanisms of action, including DNA intercalation, inhibition of DNA and RNA polymerases, and inhibition of type II topoisomerase¹⁷

• These various actions ultimately lead to halted DNA and RNA synthesis, DNA strand breakage, and cell death.¹⁷

Dose (dogs only) → 5-6 mg/m² IV q3wk (slow bolus)

• Many clinicians start at low end of dose range and escalate if the drug is well-tolerated.

Monitoring during therapy → Serial CBC evaluations

Adverse Events

• Myelosuppression^17,19
  • Neutropenia and, to a lesser degree, thrombocytopenia typically occur between 7 and 10 days postadministration.²⁰
• GI upset, typically mild^17,19

Key Points

• Causes less free-radical formation and oxidative damage as compared with doxorubicin and thus is not associated with cardiac toxicity in dogs^2,17 
  • Therefore, mitoxantrone can be used as a substitute for doxorubicin in dogs with cardiac disease and possible doxorubicin-induced cardiotoxicity.^2,17,21 
• Not associated with renal toxicity, so can be used as a substitute for doxorubicin in patients with significant renal disease¹⁷
• One study evaluated mitoxantrone as part of maintenance therapy following a standard CHOP protocol for canine lymphoma and documented longer remission and survival times as compared with historical controls.¹⁸