December 2016
Peer Reviewed

Sign in to continue reading this article

Not registered? Create an account for free to read full articles on www.cliniciansbrief.com.

To access full articles on www.cliniciansbrief.com, please sign in below.

Busy? Sign in Faster. Sign into www.cliniciansbrief.com with your social media account.

The following drugs can be used in the management of lymphoma in dogs and cats. Part 2 will discuss chlorambucil, corticosteroids (prednisone and derivatives), cytarabine, mechlorethamine, and procarbazine.

  • Asparaginase
  • Doxorubicin
  • Vincristine
  • Cyclophosphamide
  • Lomustine
  • Chlorambucil
  • Corticosteroids (prednisone and derivatives)
  • Cytarabine
  • Mechlorethamine
  • Procarbazine
  • Dacarbazine
  • Actinomycin D
  • Melphalan
  • Mitoxantrone
Common Chemotherapy Protocols
  • CHOP = cyclophosphamide, [(3)H] daunorubicin/doxorubicin, vincristine (Oncovin), prednisone
  • COP = cyclophosphamide, vincristine (Oncovin), prednisone
  • DMAC = dexamethasone, melphalan, actinomycin, cytarabine
  • MOPP = mechlorethamine, vincristine (Oncovin), procarbazine, prednisone
  • MPP = mechlorethamine, procarbazine, prednisone

Chlorambucil

Chlorambucil, an alkylating agent of the nitrogen mustard family, is most commonly used to treat indolent, small cell, low-grade GI lymphoma in cats; indolent, low-grade peripheral nodal lymphoma in dogs; and chronic lymphocytic leukemia in both dogs and cats. In addition, this drug is sometimes used as a substitute for cyclophosphamide in high-dose multiagent canine lymphoma protocols if patients have developed sterile hemorrhagic cystitis.1-5

Mechanism of action → Binds alkyl groups directly to specific sites on DNA, which leads to interstrand and intrastrand crosslinks, DNA strand breakage, disruption of DNA synthesis, and subsequent cell death1-3

Dose (dogs with indolent lymphoma) → 6 mg/m2 PO q24h for 10-14 days, then 3 mg/m2 PO q24h or q48h as maintenance2 

Dose (dogs with intermediate- to high-grade lymphoma, as substitute for cyclophosphamide when sterile hemorrhagic cystitis precludes additional cyclophosphamide doses) → 1.4 mg/kg PO once in place of cyclophosphamide in multiagent protocols2,6

Dose (cats) → 2 mg PO q48h or 20 mg/m2 PO q2-3wk4,5

Monitoring during therapy → Serial CBC evaluations

Adverse Events

  • Myelosuppression, primarily thrombocytopenia, can be cumulative and irreversible, attributable to cytotoxicity against slowly and/or noncycling hematopoietic stem cells. It may occur acutely (10-14 days postadministration) with high-dose protocols or over several months with low-dose chronic protocols.3
  • GI upset typically very mild1,3-5
  • Rarely, myoclonus has been reported as a side effect of chlorambucil use in cats.7 

Key Point

  • A very high (>95%) response rate has been reported in cats treated with chlorambucil and steroids for small cell GI lymphoma.4,5

Corticosteroids (Prednisone & Derivatives)

Prednisone, along with its derivatives prednisolone and methylprednisolone, is a catabolic steroid used as part of most chemotherapy protocols in both dogs and cats with lymphoma but carries some efficacy as a single agent against lymphocytes.2,4-6,8-16

Mechanism of action → Binds to specific cytoplasmic receptors on cancer lymphocytes, enters the nucleus, and alters DNA synthesis, which leads to apoptosis2

Corticosteroids also reduce bone resorption of calcium, reduce intestinal calcium absorption, and increase renal calcium excretion; therefore, they are useful in patients with lymphoma- associated hypercalcemia.17

Dose (dogs, as single agent in lieu of chemotherapy) → 1-2 mg/kg PO q24h continuously2,18 

Dose (dogs, as part of chemotherapy protocol) → 2 mg/kg or 40 mg/m2 PO starting dose, then tapered off over 4-6 weeks2,18

Dose (cats with indolent, small cell, low-grade GI lymphoma) → 1-2 mg/kg PO q24h continuously4 

Monitoring during therapy → Routine CBC evaluations, serum chemistry profile, urinalysis

Adverse Events18 

  • Short-term use 
    • Polyuria/polydipsia
    • Polyphagia
    • Panting, restlessness (dogs) 
    • GI ulceration with high doses 
  • Chronic use
    • Iatrogenic hyperadrenocorticism
    • Adrenal gland atrophy and iatrogenic hypoadrenocorticism after drug withdrawal
    • Iatrogenic diabetes mellitus (cats)
    • Exacerbation of underlying renal disease
    • Exacerbation of underlying cardiac disease, fluid overload (cats)
    • Proteinuria secondary to glomerular changes (dogs)
    • Muscle atrophy
    • Alopecia (dogs) 
    • GI ulceration with high doses 

Key Points

  • In cats, oral prednisolone is believed to be more bioavailable than its prodrug prednisone.18 
  • In dogs, corticosteroid use may induce partial remission.19 
    • Steroid use can also induce multidrug resistance when used as a single agent.19
      • Thus, rapid initiation of definitive therapy is paramount in dogs.20
      • However, this has not been demonstrated in cats.20 
  • Data suggest that inclusion of prednisone does not impact the overall efficacy of a multiagent protocol for lymphoma in dogs.21  
    • However, it is helpful in clinically improving systemically ill patients and may have a palliative role in patients with malignant hypercalcemia.11 

Cytarabine

Cytarabine, also known as cytosine arabinoside and ara-C, is an antimetabolite agent most commonly used as part of multiagent protocols for relapse or resistant intermediate- to high-grade lymphoma in dogs and cats. The drug can be used as part of first-line protocols for patients with known CNS involvement or as part of the multiagent DMAC (dexamethasone, melphalan, actinomycin D, cytarabine) rescue protocol or if bone marrow involvement is documented.1,2,22,23

Mechanism of action → As a pyrimidine (specifically cytidine) analog, cytarabine functions by competing with true pyrimidines for incorporation into an elongated DNA strand, thus leading to stalled DNA synthesis and subsequent cell death.22

  • Secondary mechanism of action: binding to DNA polymerase and acting as a competitive inhibitor, thus halting DNA synthesis and repair, subsequently leading to cell death22

Dose (dogs, cats) → 150-300 mg/m2 IV via CRI over 4-24 hours; 150 mg/m2 IV or SC q24h for 5 consecutive days; or 400-600 mg/m2 SC divided into 4 doses q12h over 2 days22-25 

Based on cytarabine’s mechanism of action and cell-cycle–specific nature, administration over the longest time frame is ideal; however, no prospective study comparisons of dose regimens have been performed in veterinary medicine.

Monitoring during therapy → Serial CBC evaluations 

Adverse Events

  • Myelosuppression1,2,22,23 
  • Neutropenia and thrombocytopenia typically occur 7 to 10 days postadministration. The degree of neutropenia or thrombocytopenia likely correlates with the dose regimen and is thus more likely to manifest when the drug is administered as a constant-rate infusion over a prolonged time.  
  • GI upset1,2,22 

Key Points

  • Crosses blood–brain barrier and thus has a role in treating CNS lymphoma1,2,22
  • Constant-rate infusion (but not SC administration) has been shown to achieve steady-state concentrations, thus providing higher chance of therapeutic drug concentrations crossing into the CNS when constant-rate infusion vs intermittent SC administration is used.22,24
  • In addition to use in patients with known CNS involvement, cytarabine is commonly used in cats with renal lymphoma (40%-60% chance of spread to CNS with this form).11
  • Higher complete response rate and significantly prolonged survival were documented in dogs receiving cytarabine as part of a multiagent chemotherapy protocol for lymphoma with bone marrow involvement (as compared with similarly affected dogs receiving the same protocol without cytarabine).25

Mechlorethamine

Mechlorethamine, an alkylating agent of the nitrogen mustard family, is most often used as part of the multiagent MOPP (mechlorethamine, vincristine [Oncovin], procarbazine, prednisone) protocol in the rescue setting of dogs and cats with intermediate- to high-grade lymphoma. The drug has also been evaluated as a first-line agent for treating T-cell and hypercalcemic lymphoma in dogs.1-3,13,14

Mechanism of action → Breaks down into highly reactive, positively charged intermediates that bind alkyl groups directly to specific DNA sites. This can lead to interstrand and intrastrand crosslinks, DNA strand breakage, disruption of DNA synthesis, and subsequent cell death.3

Dose (dogs, cats) → 3 mg/m2 IV

Note: This dose is in combination with other agents that make up the MOPP protocol and is generally administered on days 0 and 7 of the q3wk protocol.3,13

Monitoring during therapy → Serial CBC evaluations

Adverse Events

  • Myelosuppression1-3
    • Neutropenia typically occurs around 7 days postadministration.
  • GI upset1-3
  • Because of the potential for nausea, prophylactic antiemetics are typically given with this drug. 
  • Moderate-to-severe tissue damage if perivascular extravasation develops1,3

Key Points

  • When given as a first-line protocol for T-cell or hypercalcemic canine lymphoma, the MOPP protocol was associated with long-term survival (25% survival at >900 days).13 

Procarbazine 

Procarbazine is a methylating agent (alkylator) most commonly used as part of the multiagent MOPP protocol in the rescue setting for dogs and cats with intermediate- to high-grade lymphoma. The drug has also been evaluated as a first-line agent in the treatment of T-cell and hypercalcemic lymphoma in dogs.1,2,13,14,26

Mechanism of action → Active metabolites bind methyl groups to specific DNA sites, which can lead to DNA strand breaks, inhibition of DNA/RNA/protein synthesis, and subsequent cell death.26 

Procarbazine has been evaluated as a first-line agent in the treatment of T-cell and hypercalcemic lymphoma in dogs.1,2,13,14,26

Dose (dogs, cats) → 50 mg/m2 PO q24h, typically for 7-14 days27 

Monitoring during therapy → Serial CBC evaluations

Adverse Events

  • Myelosuppression1,2,26 
  • Because of the dose schedule and this drug’s almost exclusive use in combination protocols, it is difficult to know exactly how much of the myelosuppression seen in these patients is attributable to procarbazine.
  • GI upset1,2,26

Key Points

  • Oral bioavailability of 100%26
  • Procarbazine is a prodrug that is bioactivated to active metabolites26 by both enzymatic and nonenzymatic pathways.
  • Dose adjustments are indicated in patients with hepatic dysfunction.
  • Crosses the blood–brain barrier and thus has a role in treatment of CNS lymphoma1,2,26
References and author information Show
References
  1. Chen EX. Pharmacology of anticancer drugs. In: Tannock I, Hill R, Bristow R, Harrington L, eds. The Basic Science of Oncology. 5th ed. Toronto, Ontario: McGraw-Hill; 2013:419-442.
  2. Gustafson DL, Page RL. Cancer chemotherapy. In: Withrow SW, Vail DM, eds. Small Animal Clinical Oncology. 5th ed. St Louis, MO: Saunders Elsevier; 2013:157-179.
  3. Gerson SL, Friedman H. Alkylating agents. Part A: classical alkylating agents. In: Chabner BA, Longo DL, eds. Cancer Chemotherapy and Biotherapy: Principles and Practice. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011:267-292. 
  4. Stein TJ, Pellin M, Steinberg H, Chun R. Treatment of feline gastrointestinal small-cell lymphoma with chlorambucil and glucocorticoids. J Am Anim Hosp Assoc. 2010;46(6):413-417. 
  5. Kiselow MA, Rassnick KM, McDonough SP, et al. Outcome of cats with low-grade lymphocytic lymphoma: 41 cases (1995-2005). J Am Anim Hosp Assoc. 2008;232(3):405-410.
  6. Garrett LD, Thamm DH, Chun R, Dudley R, Vail DM. Evaluation of a 6-month chemotherapy protocol with no maintenance therapy for dogs with lymphoma. J Vet Intern Med. 2002;16(6):704-709.
  7. Benitah N, de Lorimier LP, Gaspar M, Kitchell BE. Chlorambucil-induced myoclonus in a cat with lymphoma. J Am Anim Hosp Assoc. 2003;39(3):283-287.
  8. Saba CF, Hafeman SD, Vail DM, Thamm DH. Combination chemotherapy with continuous l-asparaginase, lomustine, and prednisone for relapsed canine lymphoma. J Vet Intern Med. 2009;23(5):1058-1063.
  9. Milner RW, Peyton J, Cooke K, et al. Response rates and survival times for cats with lymphoma treated with the University of Wisconsin–Madison chemotherapy protocol: 38 cases (1996-2003). J Am Anim Hosp Assoc. 2005;227(7):1118-1122.
  10. Moore AS, Cotter SM, Frimberger AE, Wood CA, Rand WM, L’Heureux DA. A comparison of doxorubicin and COP for maintenance of remission in cats with lymphoma. J Vet Intern Med. 1996;10(6):372-375.
  11. Vail DM, Pinkerton ME, Young KM. Hematopoietic tumors. In: Withrow SW, Vail DM, eds. Small Animal Clinical Oncology. 5th ed. St Louis, MO: Saunders Elsevier; 2013:608-678.
  12. Krick EL, Cohen RB, Gregor TP, Salah PC, Sorenmo KU. Prospective trial to compare vincristine and vinblastine in a COP-based protocol for lymphoma in cats. J Vet Intern Med. 2013;27(1):134-140.
  13. Brodsky EM, Mauldin GN, Lachowicz JL, Post GS. Asparaginase and MOPP treatment of dogs with lymphoma. J Vet Intern Med. 2009;23(3):578-584.
  14. Rassnick KM, Mauldin GE, Al-Sarraf R, Mauldin GN, Moore AS, Mooney SC. MOPP chemotherapy for treatment of resistant lymphoma in dogs: a retrospective study of 117 cases (1989-2000). J Vet Intern Med. 2002;16(5):576-580. 
  15. Saba CF, Thamm DH, Vail DM. Combination chemotherapy with l- asparaginase, lomustine, and prednisone for relapsed or refractory canine lymphoma. J Vet Intern Med. 2007;21(1):127-132.
  16. Valerius KD, Ogilvie GK, Mallinckrodt CH, Getzy DM. Doxorubicin alone or in combination with asparaginase, followed by cyclophosphamide, vincristine, and prednisone for treatment of multicentric lymphoma in dogs: 121 cases (1987-1995). J Am Anim Hosp Assoc. 1997;210(4):512-516.
  17. Schenck PA, Chew DJ, Nagode LA, Rosol TJ. Disorders of calcium: hypercalcemia and hypocalcemia: In DiBartola SP, ed. Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice. 3rd ed. St Louis, MO: Saunders Elsevier; 2006:122-194.
  18. Plumb DC. Prednisolone/prednisolone sodium succinate/prednisolone acetate/prednisone. In: Plumb DC, ed. Plumb’s Veterinary Drug Handbook. 8th ed. Stockholm, WI: John Wiley & Sons; 2015.
  19. Bergman PJ, Ogilvie GK, Powers BE. Monoclonal antibody C219 immunohistochemistry against P-glycoprotein: sequential analysis and predictive ability in dogs with lymphoma. J Vet Intern Med. 1996;10(6):354-359.
  20. Brenn SH, Couto SS, Craft DM, Leung C, Bergman PJ. Evaluation of P- glycoprotein expression in feline lymphoma and correlation with clinical outcome. Vet Comp Oncol. 2008;6(3):201-211.
  21. Zandvliet M, Rutteman GR, Teske E. Prednisolone inclusion in a first-line multidrug cytostatic protocol for the treatment of canine lymphoma does not affect therapy results. Vet J. 2013;197(3):656-661.
  22. Chabner BA, Glass J. Cytidine analogues. In: Chabner BA, Longo DL, eds. Cancer Chemotherapy and Biotherapy: Principles and Practice. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011:171-191. 
  23. Alvarez FJ, Kisseberth WC, Gallant SL, Couto CG. Dexamethasone, melphalan, actinomycin D, cytosine arabinoside (DMAC) protocol for dogs with relapsed lymphoma. J Vet Intern Med. 2006;20(5):1178-1183.
  24. Crook KI, Early PJ, Messenger KM, Muñana KR, Gallagher R, Papich MG. The pharmacokinetics of cytarabine in dogs when administered via subcutaneous and continuous intravenous infusion routes. J Vet Pharmacol Therap. 2008;36(4):408-411.
  25. Marconato L, Bonfanti U, Stefanello D, et al. Cytostine arabinoside in addition to VCAA-based protocols for the treatment of canine lymphoma with bone marrow involvement: does it make a difference? Vet Comp Oncol. 2008;6(2):80-89.
  26. Friedman HS, Gerson S. Alkylating agents. Part B: methylating agents. In: Chabner BA, Longo DL, eds. Cancer Chemotherapy and Biotherapy: Principles and Practice. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011:293-309. 
  27. Brodsky EM, Maudlin GN, Lachowicz JL, Post GS. Asparaginase and MOPP treatment of dogs with lymphoma. J Vet Intern Med. 2009;23(3):578-584.
Authors

Christine Mullin

VMD, DACVIM (Oncology) Hope Veterinary Specialists, Malvern, Pennsylvania

Christine Mullin, VMD, DACVIM (Oncology), is a medical oncologist at Hope Veterinary Specialists in Malvern, Pennsylvania. She completed a 1-year internship in small animal medicine and surgery at Red Bank Veterinary Hospital in New Jersey and a 3-year residency in medical oncology at The Oncology Service in the Washington, DC, metro area. Dr. Mullin serves on the Northeast Veterinary Cooperative Oncology Group committee. Dr. Mullin received the Most Outstanding Resident Basic Science Research award at the annual Veterinary Cancer Society meeting in 2014.

Craig A. Clifford

DVM, MS, DACVIM (Oncology) Hope Veterinary Specialists, Malvern, Pennsylvania

Craig A. Clifford, DVM, MS, DACVIM (Oncology), is the director of clinical studies at Hope Veterinary Specialists in Malvern, Pennsylvania, where he also serves as a medical oncologist. Dr. Clifford earned his DVM from Mississippi State University and his MS in animal science/virology from University of Delaware, then completed an internship and a medical oncology residency at University of Pennsylvania. He has authored and coauthored more than 50 papers and book chapters. Dr. Clifford created the Veterinary Cancer Society’s resident review session and the Northeast Veterinary Cooperative Oncology Group and has served on the VCS executive board, ACVIM Examination Rating Committee, Residency Training and Credentials Committee, Oncology Pathology Working Group, Standards of Excellence in Residency Education Task Force, and Australian Scientist’s Oncology Specialty Examination. Dr. Clifford also serves on the Scientific Advisory Boards for Industry. 

Material from Clinician’s Brief may not be reproduced, distributed, or used in whole or in part without prior permission of Educational Concepts, LLC. For questions or inquiries please contact us.

Up Next