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Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is a hematopoietic tumor of B-cells. It is the most common type of non-Hodgkin lymphoma in both people and dogs, with an annual incidence of 15.5-29.9 per 100,000 people and 15-30 per 100,000 dogs. 

Description

Diffuse large B-cell lymphoma (DLBCL) is a hematopoietic tumor of B-cells. It is the most common type of non-Hodgkin lymphoma in both people and dogs, with an annual incidence of 15.5-29.9 per 100,000 people and 15-30 per 100,000 dogs. 

Similarities in humans

Canine and human lymphoma (DLBCL) share many important features, including shared molecular and genetic changes, and histologic appearance. Additionally, the disease is clinically very similar between species, with an analogous disease presentation, treatment options, and response to treatment.

Differences in humans

While many of the treatment modalities used in human DLBCL are also used in dogs, there are some differences in the treatment options currently available, which can influence the way that treatment decisions are made. For example, rituximab is a monoclonal antibody that recognizes the CD20 antigen on B-cells. It is commonly used as part of a treatment regimen in people with DLBCL, however this drug does not recognize the canine CD20 protein and is therefore not included in the treatment protocols in dogs.

Disease etiology

While any dog can develop DLBCL, several breeds are more likely to develop DLBCL in comparison to other subtypes of lymphoma; such as Rottweilers, Doberman pinchers and Cocker Spaniels. The cause of DLBCL is not well-understood, however several immunologic risk factors have been identified, including immunosuppression associated with immune-mediated disease (e.g. immune mediated thrombocytopenia) and renal transplantation. In people, a viral etiology associated with the Epstein Barr herpes virus (EBV) is described in up to 15% of DLBCL cases. While EBV has been documented in dogs, there is no confirmed retroviral involvement in the pathogenesis of canine DLBCL. 

Clinical presentation

Clinical signs of DLBCL are commensurate with the stage of disease and anatomic structures involved in the disease process. The first sign of disease is often peripheral lymphadenopathy, with constitutional signs (lethargy, fever, weight loss, inappetence) becoming more prevalent in dogs with a larger burden of disease.

Treatment

As in people, multi-agent chemotherapy protocols are typically used to treat dogs with DLBCL. The most commonly used regimen involves a combination of vincristine, cyclophosphamide, prednisone and doxorubicin (e.g. CHOP-based chemotherapy). The addition of rituximab, an anti-CD20 monoclonal antibody, is standard in people. While not historically available to veterinary patients, canine specific anti-CD20 monoclonal antibodies are currently under clinical investigation. Approximately 88-95% of dogs will experience a complete response to CHOP-based chemotherapy, leading to median survival times of 10-14 months in dogs with DLBCL. The breed predispositions and clinical and molecular similarities of DLBCL in people and dogs, support the continued use of dogs as a model to study biologic features of disease and investigate novel therapeutics.

Recent Publications

1. Murthy SL, Hitchcock MA, Endicott-Yazdani TR, Watson JT, Krause JR. Epstein-Barr virus-positive diffuse large B-cell lymphoma. Proc (Bayl Univ Med Cent). 2017;30(4):443-4. Epub 2017/10/03. PubMed PMID: 28966459; PMCID: PMC5595389.

2. Waugh EM, Gallagher A, McAulay KA, Henriques J, Alves M, Bell AJ, Morris JS, Jarrett RF. Gammaherpesviruses and canine lymphoma: no evidence for direct involvement in commonly occurring lymphomas. J Gen Virol. 2015;96(Pt 7):1863-72. Epub 2015/02/28. doi: 10.1099/vir.0.000106. PubMed PMID: 25722346; PMCID: PMC4635455.

3. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J, Jr., Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Levy R, Wilson W, Grever MR, Byrd JC, Botstein D, Brown PO, Staudt LM. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403(6769):503-11. Epub 2000/02/17. doi: 10.1038/35000501. PubMed PMID: 10676951.

4. Frantz AM, Sarver AL, Ito D, Phang TL, Karimpour-Fard A, Scott MC, Valli VE, Lindblad-Toh K, Burgess KE, Husbands BD, Henson MS, Borgatti A, Kisseberth WC, Hunter LE, Breen M, O’Brien TD, Modiano JF. Molecular profiling reveals prognostically significant subtypes of canine lymphoma. Vet Pathol. 2013;50(4):693-703. Epub 2012/11/06. doi: 10.1177/0300985812465325. PubMed PMID: 23125145; PMCID: PMC4683027.

5. Richards KL, Motsinger-Reif AA, Chen HW, Fedoriw Y, Fan C, Nielsen DM, Small GW, Thomas R, Smith C, Dave SS, Perou CM, Breen M, Borst LB, Suter SE. Gene profiling of canine B-cell lymphoma reveals germinal center and postgerminal center subtypes with different survival times, modeling human DLBCL. Cancer Res. 2013;73(16):5029-39. doi: 10.1158/0008-5472.CAN-12-3546. PubMed PMID: 23783577; PMCID: PMC3755352.

6. Davis RE, Brown KD, Siebenlist U, Staudt LM. Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med. 2001;194(12):1861-74. Epub 2001/12/19. PubMed PMID: 11748286; PMCID: PMC2193582.

7. Gardner HL, Fenger JM, London CA. Dogs as a Model for Cancer. Annu Rev Anim Biosci. 2016;4:199-222. doi: 10.1146/annurev-animal-022114-110911. PubMed PMID: 26566160.

8. Bushell KR, Kim Y, Chan FC, Ben-Neriah S, Jenks A, Alcaide M, Fornika D, Grande BM, Arthur S, Gascoyne RD, Steidl C, Morin RD. Genetic inactivation of TRAF3 in canine and human B-cell lymphoma. Blood. 2015;125(6):999-1005. doi: 10.1182/blood-2014-10-602714. PubMed PMID: 25468570.

9. Elvers I, Turner-Maier J, Swofford R, Koltookian M, Johnson J, Stewart C, Zhang CZ, Schumacher SE, Beroukhim R, Rosenberg M, Thomas R, Mauceli E, Getz G, Palma FD, Modiano JF, Breen M, Lindblad-Toh K, Alfoldi J. Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background. Genome Res. 2015;25(11):1634-45. doi: 10.1101/gr.194449.115. PubMed PMID: 26377837; PMCID: PMC4617960.

10. Arico A, Ferraresso S, Bresolin S, Marconato L, Comazzi S, Te Kronnie G, Aresu L. Array-based comparative genomic hybridization analysis reveals chromosomal copy number aberrations associated with clinical outcome in canine diffuse large B-cell lymphoma. PLoS One. 2014;9(11):e111817. Epub 2014/11/06. doi: 10.1371/journal.pone.0111817. PubMed PMID: 25372838; PMCID: PMC4221131.

11. Harrington BK, Gardner HL, Izumi R, Hamdy A, Rothbaum W, Coombes KR, Covey T, Kaptein A, Gulrajani M, Van Lith B, Krejsa C, Coss CC, Russell DS, Zhang X, Urie BK, London CA, Byrd JC, Johnson AJ, Kisseberth WC. Preclinical Evaluation of the Novel BTK Inhibitor Acalabrutinib in Canine Models of B-Cell Non-Hodgkin Lymphoma. PLoS One. 2016;11(7):e0159607. doi: 10.1371/journal.pone.0159607. PubMed PMID: 27434128; PMCID: PMC4951150.

12. Gardner HL, Rippy SB, Bear MD, Cronin KL, Heeb H, Burr H, Cannon CM, Penmetsa KV, Viswanadha S, Vakkalanka S, London CA. Phase I/II evaluation of RV1001, a novel PI3Kdelta inhibitor, in spontaneous canine lymphoma. PLoS One. 2018;13(4):e0195357. Epub 2018/04/25. doi: 10.1371/journal.pone.0195357. PubMed PMID: 29689086; PMCID: PMC5915681.

13. Saba CF, Vickery KR, Clifford CA, Burgess KE, Phillips B, Vail DM, Wright ZM, Morges MA, Fan TM, Thamm DH. Rabacfosadine for relapsed canine B-cell lymphoma: Efficacy and adverse event profiles of 2 different doses. Vet Comp Oncol. 2018;16(1):E76-E82. Epub 2017/09/12. doi: 10.1111/vco.12337. PubMed PMID: 28891260.

14. Thamm DH, Vail DM, Post GS, Fan TM, Phillips BS, Axiak-Bechtel S, Elmslie RS, Klein MK, Ruslander DA. Alternating Rabacfosadine/Doxorubicin: Efficacy and Tolerability in Naive Canine Multicentric Lymphoma. J Vet Intern Med. 2017;31(3):872-8. Epub 2017/04/04. doi: 10.1111/jvim.14700. PubMed PMID: 28370378; PMCID: PMC5435064.

15. Curran KM, Schaffer PA, Frank CB, Lana SE, Hamil LE, Burton JH, Labadie J, Ehrhart EJ, Avery PR. BCL2 and MYC are expressed at high levels in canine diffuse large B-cell lymphoma but are not predictive for outcome in dogs treated with CHOP chemotherapy. Vet Comp Oncol. 2017;15(4):1269-79. Epub 2016/08/16. doi: 10.1111/vco.12263. PubMed PMID: 27514648.

16. Shi QY, Feng X, Bao W, Ma J, Lv JH, Wang X, Rao Q, Shi QL. MYC/BCL2 Co-Expression Is a Stronger Prognostic Factor Compared With the Cell-of-Origin Classification in Primary CNS DLBCL. J Neuropathol Exp Neurol. 2017;76(11):942-8. Epub 2017/10/19. doi: 10.1093/jnen/nlx083. PubMed PMID: 29044419.

17. Koshino A, Goto-Koshino Y, Setoguchi A, Ohno K, Tsujimoto H. Mutation of p53 Gene and Its Correlation with the Clinical Outcome in Dogs with Lymphoma. J Vet Intern Med. 2016;30(1):223-9. doi: 10.1111/jvim.13807. PubMed PMID: 26678182; PMCID: PMC4913626.

18. Wilson WH, Teruya-Feldstein J, Fest T, Harris C, Steinberg SM, Jaffe ES, Raffeld M. Relationship of p53, bcl-2, and tumor proliferation to clinical drug resistance in non-Hodgkin’s lymphomas. Blood. 1997;89(2):601-9. Epub 1997/01/15. PubMed PMID: 9002964.

INVESTIGATORS

Lauren Trepanier