Bone marrow transplantation in canine lymphoma

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					Australian College of Veterinary Scientists – Science Week 2004 – Small Animal Medicine Chapter meeting

                     Bone marrow transplantation in canine lymphoma
                      Angela E. Frimberger, VMD, Diplomate ACVIM (Oncology)
                              Director, Veterinary Oncology Consultants
                             379 Lake Innes Drive, Wauchope, NSW 2446
                                    www.vetoncologyconsults.com

     Introduction
     Lymphoma is the most common malignancy that involves cells of the haematopoietic system,
     and it is the most responsive to chemotherapy. The most common physical finding in dogs
     with lymphoma is peripheral lymphadenopathy, which is usually generalized but may be
     localized to a single lymph node or a region of the body. Involvement of other organs, such as
     spleen, liver, or bone marrow is an indication of advanced disease. Involvement of other
     (extranodal) sites is rare in dogs. Most commonly, there are few, if any, clinical signs of
     illness, although owners may report reduced exercise tolerance, fatigability, and mild
     inappetence. This is in contrast with most systemic infections (e.g., fungal, bacterial,
     rickettsial, viral, and protozoal) that cause obvious signs of illness, as do immune-mediated
     diseases causing lymphadenopathy. Lymphoma should always be suspected in a middle-aged,
     apparently healthy dog with lymphadenopathy. If the disease is advanced and involves other
     organs, dogs may show weakness, depression, anorexia, vomiting, or diarrhea. Terminally ill
     dogs may be cachectic, dyspnoeic due to respiratory tract obstruction by lymph nodes, pyrexic
     (dogs with lymphoma are immunocompromised and therefore are at high risk of developing
     severe infections, such as pneumonia), and have episodes of collapse.

     Untreated lymphoma progresses rapidly (1–2 months) from presentation to terminal stages.
     With chemotherapy, however, considerable improvement in the duration and quality of the
     patient’s life can be expected.

     Staging and Diagnosis
     When evaluating an animal for treatment of lymphoma, it is important not only to obtain a
     definitive diagnosis but also to assess the general health of the patient by clinical examination
     and ancillary diagnostics. Lymphoma is a systemic disease; therefore, it is important to
     determine the extent of organ involvement with lymphoma and to identify unrelated or
     secondary conditions that need to be treated or controlled before instituting appropriate
     therapy.

     The diagnosis of lymphoma can be confirmed by cytologic or histologic demonstration of
     malignant lymphoid infiltration in organs that do not ordinarily contain such cells. Cytologic
     examination of lymph nodes may be suggestive of, or compatible with, a diagnosis of
     lymphoma but rarely provides a definitive diagnosis. In the presence of lymphadenopathy, a
     definitive diagnosis of lymphoma is based on histologic examination of a surgically resected
     lymph node. This is preferable to a needle or wedge biopsy because an entire lymph node can
     be examined for key histopathologic evidence of malignancy, such as disruption of
     architecture and invasion of the capsule. Examination of nodal architecture enables the
     pathologist to assign a grade, which is important for prognosis. T- and B-cell markers should
     be requested to determine the immunophenotype of the lymphoma, which is an important
     prognostic indicator. The most accessible, most easily removed lymph node is the popliteal
     lymph node.

     Staging is a clinical process that enables the veterinarian to quantitate the extent of lymphoma
     involvement in the patient. Staging carries prognostic significance and enables the
     veterinarian and client to make informed and rational decisions as to the type of therapy best
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Australian College of Veterinary Scientists – Science Week 2004 – Small Animal Medicine Chapter meeting

     suited for the patient. In dogs, the most widely used scheme is the one developed by the
     World Health Organization. Each dog is clinically staged based on the results of physical
     examination, clinical laboratory testing (i.e., CBC, biochemical profile, urinalysis, and bone
     marrow cytology), and imaging procedures (i.e., radiography and ultrasonography).

     Prognostic Factors
     General statistics for survival of canine lymphoma patients can be derived from reports of the
     efficacy of different chemotherapy protocols, but there is little information available to help
     form a prognosis for the individual patient. As more information becomes available, it is
     becoming clear that good clinical staging and ancillary laboratory testing provide important
     prognostic information. Prognostic factors include stage and substage of disease, histologic
     type, immunophenotype (B-cell versus T-cell), presence of hypercalcaemia, response to
     therapy, pretreatment steroid therapy, and possibly gender. In the future, histopathologic
     “subtyping” of lymphoma using specific antibodies and cell markers may provide prognostic
     information for individual patients. Currently, the most useful information is complete stage
     and substage, and immunophenotype.

     Treatment
     Once a definitive diagnosis has been obtained and after the patient has been staged accurately,
     the veterinarian should schedule a discussion with the owner regarding prognosis and
     treatment. One of the most important distinctions to make for the client is between remission
     and cure. When toxicities are discussed, the owner should be given criteria by which to
     distinguish mild side effects from those that can be life-threatening. A copy of the protocol to
     be administered, with scheduled treatments, rechecks, and blood counts, will assist owners in
     remembering much of the information they receive at this time.

     It is important that the client be given all the options and that the best option is used first. As a
     general rule, combination chemotherapy is superior to single-agent therapy. Each time an
     effective drug is added to the COP protocol, the remission time improves. Although the
     remission time increases with the addition of a drug, so do the cost and the potential for
     toxicity. It is also important that clients realize that a second or third remission is possible
     with appropriate therapy. These subsequent remissions are more difficult to attain and their
     duration is generally half the duration of the previous remission.

     By far, the most effective chemotherapy protocols to date use a five-drug combination of L-
     asparaginase, vincristine, cyclophosphamide, doxorubicin, and prednisolone. Similar
     remission rates and survival times have been obtained for the protocols detailed as ACOPA-1,
     AMC-2, Madison-Wisconsin, and VELCAP (Tufts). The protocol ACOPA-2 is not
     recommended. Although these protocols require more intense client–veterinarian
     communication and monitoring for toxicity; the overall level of satisfaction for owners, pets,
     and veterinarians is high.

     Bone Marrow Transplantation in Canine Lymphoma
     High-dose chemotherapy with haematopoietic stem cell (HSC) support, or bone marrow
     transplantation (BMT), is important in the therapy of lymphoma and other malignancies in
     humans. Since most chemotherapy drugs exhibit a dose-response relationship, increased dose
     intensity should result in increased efficacy, and strong clinical evidence in cancer patients
     supports this. However, the clinical utility of dose intensification is limited by the toxicity of
     the regimen. Most myeloablative BMT protocols offer significantly higher cure rates than
     those seen with standard therapy, but with significantly increased toxicity. In recent years it
     has become clear that nonmyeloablative stem cell transplantation may have advantages. The
     rationale is to increase the chemotherapeutic dose intensity above standard, thereby improving

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Australian College of Veterinary Scientists – Science Week 2004 – Small Animal Medicine Chapter meeting

     antitumour efficacy, without incurring the level of toxicity associated with myeloablation.
     This could make the approach much more tolerable while still exposing tumour cells to
     increased cytotoxic dose intensity compared to standard regimens.

     We have sought to document that dogs with lymphoma can receive a clinical benefit without a
     concomitant increase in toxicity, from moderately dose-intensified chemotherapy with
     autologous bone marrow support. Our goal has been to increase the tolerable dose of
     chemotherapy agents in order to allow patients to receive the highest possible chemotherapy
     dose intensity while still enjoying the best possible quality of life and lowest possible risk of
     complications. We hypothesized that autologous BMT would allow dogs to receive
     intensified doses of myelosuppressive chemotherapy without increased toxicity, and that this
     intensification would improve remission duration and overall survival.

     The protocol is based on an established standard dose chemotherapy protocol. Dogs in
     complete remission at week 8 receive G-CSF for 1 week. The following day bone marrow is
     collected and cryopreserved. Harvesting bone marrow from dogs is quick, simple, and safe in
     our experience, and adequate cell yields are easily obtainable. Two weeks later dogs receive a
     single intravenous dose of cyclophosphamide with mesna. Starting 48 hours later, the
     cryopreserved bone marrow is administered intravenously. Dogs receive prophylactic
     antibiotics starting on the day of high dose chemotherapy, and complete blood cell counts are
     monitored. After marrow recovery, dogs are examined regularly. Remission length is
     measured from the date of starting chemotherapy to the date of clinical relapse.

     To date, 28 dogs have been treated with 3 different dosage levels of cyclophosphamide: 300
     mg/m2 (group 1), 400 mg/m2 (group 2), and 500 mg/m2 (group 3). Toxicity has been
     acceptable overall, with only one dog requiring hospitalization for complications after
     transplant that resolved in 24 hours. All other dogs were managed on a fully outpatient basis.
     Remission duration was similar for groups 1 and 2. For group 3, the remission duration was
     longer than for group 2.

     Using autologous bone marrow to support chemotherapy dose intensification allows dogs to
     receive 2.5 times the standard dose of cyclophosphamide without any increase in clinical
     toxicity, and this dose intensification results in substantial prolongation of remission and
     improved survival in canine lymphoma patients.

     References
     Dorn C, Taylor D, Schneider R: The epidemiology of canine leukemia and lymphoma. Bibl Haemat 36:403–415,
     1970.
     Owen L: TNM Classification of Tumours in Domestic Animals. Geneva, World Health Organization, pp 46–47,
     1980.
     Kiupel M, Teske E, Bostock D. Prognostic factors for treated canine malignant lymphoma. Vet Pathol 36:292-
     300, 1999.
     Cotter S: Treatment of lymphoma and leukemia with cyclophosphamide, vincristine, and prednisolone: I.
     Treatment of dogs. JAAHA 19:159–165, 1983.
     Moore AS, Cotter SM, Rand WM, Wood CA, Williams LE, London CA, Frimberger AE, L’Heureux DA.
     Evaluation of a discontinuous treatment protocol (VELCAP-S) for canine lymphoma. J Vet Int Med 15:348-
     354,2001.




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