Treatment options for canine lymphoma

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Lymphoma, a cancer that originates in white blood cells, is one of the most common cancers in canines. Most dogs diagnosed with lymphoma have the intermediate or high-grade form of the disease, but given recent advances in molecular diagnostics, other previously underrecognized subtypes, like indolent lymphoma, are being more frequently diagnosed.

Upon diagnosis or suspicion of lymphoma, patients typically undergo a series of staging tests, including lab work (CBC and chemistry panel), fine needle aspiration cytology and/or biopsy, imaging (ultrasound and/or thoracic radiographs), and molecular diagnostics (immunohistochemistry, immunocytochemistry, PCR for antigen receptor rearrangement, flow cytometry, and genomic profiling) to determine the nature and extent of disease. This allows them to be categorized by disease stage (I-V), substage (a or b), cell size/grade (large cell, intermediate grade, high grade, or small cell/low-grade/indolent), and immunophenotype (B cell or T cell). Most patients present with at least stage III disease, with generalized peripheral lymphadenopathy. Stage IV involves hepatosplenic involvement, and stage V refers to the presence of bone marrow infiltration or involvement of extranodal sites like the kidneys, lungs, CNS, or eyes. Clinically ill (substage b) dogs and dogs with advanced (stage V) disease typically have a poorer long-term prognosis. Of additional importance is immunophenotype, which can provide prognostic information and guide therapy. B cell is the most common intermediate to high-grade form, whereas T-cell lymphoma is less common but more frequently seen in breeds like Boxers, Golden Retrievers, and Siberian Huskies. T-cell disease is associated with certain anatomic forms, including cutaneous, mediastinal, hepatic, and gastrointestinal.¹

Treatment

For many years, the standard of care for most canine lymphomas has been doxorubicin-based combination chemotherapy, or CHOP. The acronym comprises the names of the 4 drugs that make up the protocol: cyclophosphamide, hydroxydaunorubicin (doxorubicin), Oncovin (vincristine), and prednisone.² There are well over a dozen published protocols that differ in the number of drugs used and the timing of each drug. Typically, protocol length varies from 12 weeks to more than 2 years and is often driven by efficacy, cost, and owner convenience. These authors currently treat dogs with a 16-week protocol that is broken down into four 4-week cycles. Afterward, patients are monitored every 4 to 8 weeks. Because T-cell lymphoma has a poorer response to doxorubicin-based chemotherapy, many oncologists will modify the protocol by substituting it with alkylating agents.³ To date, no prospective head-to-head studies have demonstrated what protocol performs best for T-cell lymphoma.

In select cases, less intensive alternatives to standard CHOP-based chemotherapy may be chosen: single-agent doxorubicin or lomustine (CCNU) +/- L-asparaginase, and prednisone for palliative care. Several rescue protocols exist and can be employed in the event of a relapse during or following CHOP-based chemotherapy.

What’s new?

Tanovea

Tanovea (rabacfosadine for injection, Elanco) became the first fully FDA-approved drug for canine lymphoma in 2021. It is indicated for the treatment of lymphoma without specification as to immunophenotype, anatomic site, stage/substage, or degree of pretreatment. It is not a substrate for P-glycoprotein and therefore should not be subject to the multidrug resistance that commonly develops in dogs treated with doxorubicin-based chemotherapy.

Tanovea is given as a 30-minute IV infusion once every 3 weeks at a dose of 1 mg/kg for up to 5 consecutive doses. Common side effects include gastrointestinal and hematologic changes similar to those seen with other chemotherapy agents. Incremental dose reductions or dose delays may be used to manage adverse reactions. There are 2 toxicities specific to Tanovea: a cumulative dermatopathy characterized by local superficial erythema and pruritus, most often in the periauricular region, dorsum, and inguinal region. This typically resolves with drug discontinuation and supportive therapies. A small number of dogs (~4%) have developed pulmonary fibrosis as a late complication (months after study completion, while in remission), so careful monitoring with thoracic radiographs has been recommended.^4-6 Based upon its high response rate and duration of response, Tanovea is an excellent first rescue drug, particularly for B-cell lymphoma.⁶ Furthermore, the data from a study that alternated Tanovea and doxorubicin in previously untreated patients is compelling, and this option may be a viable first-line option for those owners who make treatment decisions partly based on the number of visits.⁷

Laverdia-CA1

Laverdia-CA1 (verdinexor tablets, Dechra) is the first oral treatment for dogs with lymphoma conditionally approved by the FDA. Verdinexor is a selective inhibitor of nuclear export (SINE) and thus can induce apoptosis and enhance antiproliferation of cancer cells, sensitize cancer cells to chemotherapeutic agents, and reverse drug resistance in some cases.⁸ Verdinexor is not cytotoxic or myelosuppressive and is relatively targeted to neoplastic cells. Like Tanovea, it is not a substrate for P-glycoprotein and should not lead to multidrug resistance.

Laverdia-CA1 comes in 2.5-mg, 10-mg, and 50-mg tablets and is conveniently administered orally by the owner twice a week. The majority of side effects are low-grade, with the most common being anorexia, weight loss, lethargy, and diarrhea. Doses can be modified to manage adverse events and enhance/maintain clinical response.⁹

Clinical data on the use of Laverdia-CA1 in dogs is limited, but its efficacy as a single-agent treatment for multiple types of canine lymphoma has demonstrated in multiple clinical scenarios, including B-cell, T-cell, naïve, and first relapse lymphomas following either single or multi-agent protocols. In a phase 2 study, its overall clinical benefit rate was 55%, with a median duration of benefit of 71 days (range, 21-273 days). T-cell lymphoma, traditionally more refractory to conventional treatment, was associated with a clinical benefit rate of 71%, regardless of whether the lymphoma was naïve or relapsed.¹⁰ The pivotal trial for Laverdia-CA-1 to obtain full approval is ongoing at several US sites. Researchers think this SINE may be worth investigating when¹¹:

• Owners elect against referral and want to do more than prednisone alone.
• Patient is to be referred, but referral is several weeks away.
• Patient has failed SOC chemotherapy, and owner elects against other chemotherapy protocols.
• Patient has failed multiple protocols, and owner is only looking for more time.
• Patients have recently completed CHOP, have many poor indicators, and there is a concern they may relapse early.
• Epitheliotropic lymphoma relapses, or the owner elects against CCNU.
• Indolent lymphoma progresses.
• Lymphoma is atypical (small-cell, null-cell, intermediate grade, etc.)

Summary

The future is bright for dogs with lymphoma, as our industry partners are bringing in new and more novel therapies for patients with the disease. The ultimate place for these agents is still under investigation, but we now have a more options for the treatment of canine lymphoma.

References

1. Vail DM et al. Hematopoietic tumors, section a: canine lymphoma and lymphocytic leukemias. InVail DM, Thamm D, Liptak J. Saunders, eds. Withrow and MacEwen’s Small Animal Clinical Oncology. 6th ed. Elsevier;2019:688-712.
2. 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. doi:10.1892/0891-6640(2002)016<0704:eoacpw>2.3.co;2
3. Regan RC, Kaplan MS, Bailey DB. Diagnostic evaluation and treatment recommendations for dogs with substage-a high-grade multicentric lymphoma: results of a survey of veterinarians. Vet Comp Oncol. 2013;11(4):287-295. doi:10.1111/j.1476-5829.2012.00318.x
4. Weishaar KM, Wright ZM, Rosenberg MP, et al. Multicenter, randomized, double-blinded, placebo-controlled study of rabacfosadine in dogs with lymphoma. J Vet Intern Med. 2022;36(1):215-226. doi:10.1111/jvim.16341
5. Saba CF, Clifford C, Burgess K, et al. Rabacfosadine for naïve canine intermediate to large cell lymphoma: Efficacy and adverse event profile across three prospective clinical trials. Vet Comp Oncol. 2020;18(4):763-769. doi:10.1111/vco.12605
6. Saba CF, Vickery KR, Clifford CA, et al. Rabacfosadine for relapsed canine B-cell lymphoma: efficacy and adverse event profiles of 2 different doses. Vet Comp Oncol. 2018;16(1):E76-E82. doi:10.1111/vco.12337
7. Thamm DH, Vail DM, Post GS, et al. Alternating rabacfosadine/doxorubicin: efficacy and tolerability in naïve canine multicentric lymphoma. J Vet Intern Med. 2017;31(3):872-878. doi:10.1111/jvim.14700
8. London CA, Bernabe LF, Barnard S, et al. Preclinical evaluation of the novel, orally bioavailable selective inhibitor of nuclear export (SINE) KPT-335 in spontaneous canine cancer: results of a phase I study. PLoS One. 2014;9(2):e87585. doi:10.1371/journal.pone.0087585
9. Laverdia-CA1 Package Insert, Anivive Lifesciences, 2020.
10. Bergman, PJ, Clifford CA, Thamm D, Johannes C. Clinical integration of Tanovea® and Laverdia™-ca1 for canine lymphoma. Presented at: 2022 ACVIM Forum; June 23-25; Austin TX.
11. Sadowski AR, Gardner HL, Borgatti A, et al. Phase II study of the oral selective inhibitor of nuclear export (SINE) KPT-335 (verdinexor) in dogs with lymphoma. BMC Vet Res. 2018;14(1):250. doi:10.1186/s12917-018-1587-9