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Horses

Lymphoproliferative and Myeloproliferative Disorders

Leukemia is the abnormal proliferation of hematopoietic cells that encompasses both lymphoproliferative and myeloproliferative disorders and is considered rarer in the horse than in other species. Leukemia can be classified based on the (1) type of abnormal cell: lymphoid or myeloid; (2) degree of tumor differentiation: acute or chronic; and (3) number of specific types of abnormal cells that are circulating in the peripheral blood: aleukemic, subleukemic, or leukemic. In addition, tumor cells can be further characterized by histochemical and immunohistologic methods. The lymphoproliferative (lymphoma, lymphoid leukemia, and plasma cell myeloma) and myeloproliferative (the myeloid leukemias and erythrocytosis) disorders of the horse are reviewed in this post.

Lymphoma

Plasma Cell Myeloma

Plasma cells are terminally differentiated B cell lymphocytes. Malignant transformation can result in three categories of tumors: chronic B cell lymphocytic leukemia, B cell lymphoma (considered above), and plasma cell tumors. Plasma cell tumors occur rarely in the horse; most of the reported information is derived from individual cases and a retrospective series of 10 cases (). No risk factors have been established, and affected animals have ranged from 3 months to 22 years of age. Solitary plasmacytoma is the term used for a single extramedullary tumor. However, the most common form of plasma cell tumors in horses involves the bone marrow and is called multiple myeloma.

Plasma Cell Myeloma: Clinical Signs

Clinical signs are associated with the sites of tumor invasion and include limb edema, ataxia, lameness, epistaxis, lymphadenopathy, weight loss, and anorexia. Secondary infections that commonly involve the lower respiratory or urinary tract may develop. Anemia and hyperglobulinemia are the most common abnormal laboratory findings. With myelophthisic disease, the anemia may be severe and accompanied by leukopenia and thrombocytopenia. Hypoalbuminemia may accompany hyperglobulinemia. A monoclonal gammopathy is detected in nearly all cases by serum electrophoresis and reflects the malignant transformation and clonal expansion of a single plasma cell lineage. The monoclonal protein, called a paraprotein, may be a complete or partial immunoglobulin, the majority of which are in the IgG class. Analysis of urine may reveal proteinuria, and the heat-precipitation method has confirmed the presence of light chains (Bence Jones protein) in the urine of a few horses. Occasionally, hypercalcemia may be found as a paraneoplastic condition.

Diagnosis of Plasma Cell Myeloma

In human patients, definitive diagnosis is based on the demonstration of bone marrow plasmacytosis (>10% of cells) or an extramedullary plasmacytoma and one of the following: (1) a serum monoclonal gammopathy; (2) detection of a urine monoclonal protein; or (3) osteolytic lesions. The majority of equine cases have a monoclonal gammopathy; however, cases in which the serum globulin content was within normal limits have been described. Further examinations should include skeletal survey radiographs of the long bones and cervical vertebrae and biochemical tests to detect renal or hepatic involvement.

Prognosis and Treatment of Plasma Cell Myeloma

Most horses die or are euthanized within 4 months of developing clinical signs, but longer survival times have been reported in a few horses treated with antineoplastic agents. Melphalan (Alkeran), prednisone, and cyclophosphamide have been used in the treatment of multiple myeloma in an 18-year-old Quarter Horse mare. Diagnosis was confirmed 1 week before foaling. Chemotherapy was started after the foal was weaned at 4 days of age; however, dosages were not reported, and plasmapheresis was also performed. The mare was euthanized 7 months after diagnosis because of severe chronic laminitis. A 20-year-old horse with multiple myeloma was also treated with melphalan (7 mg/mz PO q24h for 5 days, and then every 3 weeks). The horse’s condition remained stable for 1 year after diagnosis.

Myeloid Leukemias

Myeloproliferative disorders are characterized by medullary and extramedullary proliferation of bone marrow constituents, including the erythroid, granulocytic, monocytic, and megakaryocytic cell series. Myelodysplastic syndromes are characterized by refractory cytopenia, which generally progresses to acute myeloid leukemia. Classification schemes for myeloid leukemia are based on the degree of differentiation of the transformed cell line. For example, chronic myeloid leukemia involves neutrophils and late precursor cells, whereas acute myeloid leukemia involves myeloblast cells. In general, chronic leukemias are less aggressive than acute leukemias. Reports of myeloproliferative disorders of horses are rare and are dominated by acute leukemias of the granulocytic cell series.

Clinical Signs of Myeloid Leukemias

In a review of 11 reported cases of myelogenous leukemia in the horse, the ages ranged from 10 months to 16 years, and both genders and various breeds were affected. Common clinical findings included ventral and peripheral edema, petechiae, weight loss, depression, and enlarged lymph nodes. Less common findings were fever, epistaxis, pneumonia, exercise intolerance, and colic. All were found to be anemic and thrombocytopenic and had circulating neoplastic cells; the majority had neutropenia and a gammopathy. Secondary infections seem more common in this form of hematopoietic disorders, presumably as a result of immunosuppression. Two horses with myelomonocytic leukemia developed pulmonary aspergillosis.

Diagnosis of Myeloid Leukemias

Bone marrow examination confirms the diagnosis. Confirmation of cell lineage may be morphologically obvious. When needed, further characterization is possible with histochemical and immunohistologic or flow cytometric identification of cell-surface antigens or enzyme content.

Myeloid Leukemias: Prognosis and Therapy

Myelogenous leukemias are notoriously resistant to common antineoplastic agents. However, chemotherapy has been attempted in at least two cases of equine acute myelomonocytic leukemia. These horses were given cytosine arabinoside, based on a low-dose protocol (10 mg/m2 q12h for 3 weeks) adopted from human cancer medicine. The aim of this therapy is to promote terminal differentiation of the neoplastic cell line and diminish clonal expansion. Newer modalities are being tested in human patients and include the use of hematopoietic cytokines and bone marrow transplantation, but no reports of similar use in equine cancer patients exist.

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Horses

Lymphoma

Lymphoma is the general term denoting malignant transformation of lymphoid cells, but it is often used in equine medicine in place of the term lymphosarcoma, which is specifically the malignant transformation of lymphoid cells into solid (or sarcomatous) tumors. Lymphoid leukemia (or “true” leukemia) denotes the malignant transformation of lymphoid cells within the bone marrow. Both forms of lymphoid neoplasia may be accompanied by circulating neoplastic cells.

Lymphoma is one of the most common internal neoplasms of the horse, but the prevalence of lymphoma in horse populations is relatively low — ranging from 0.002% to 0.05%, based on United States abattoir surveys and from 0.2% to 3.0%, based on necropsy surveys. No established risk factors for equine lymphoma exist, and the etiology is unknown. A breed or sex predilection does not appear to be a factor, and the majority of patients are between 4 and 10 years of age. However, individual cases of lymphoma in a fetus and in horses younger than 1 year or older than 20 years of age have been reported.

Clinical Signs of Lymphoma

A diverse spectrum of clinical signs has been associated with lymphoma. The signs and progression of disease relate to the sites of tumor involvement and are not specific to lymphoma. The most common clinical signs are decreased appetite, depression, weight loss, fever, lymphadenopathy, and dependent edema. In a study of 20 cases of lymphoma confirmed by histology, the clinical findings included — in descending order of frequency — weight loss, fever, peripheral lymphadenopathy, abdominal mass, upper or lower respiratory signs, ocular signs, colic, and diarrhea.

Numerous lymphoma tumor locations have been reported and include peripheral and internal lymph nodes, spleen, liver, kidney, intestine, heart, lung, nasopharynx, eye and adnexa, skeletal muscle, skin, reproductive organs, and central and peripheral nervous system. Four anatomic forms of lymphoma are well described: multi-centric — 50%; alimentary — 19%; mediastinal — 6%; and extranodal — 25%. Combinations of these four classic forms of lymphoma occur in approximately 50% of cases.

Multicentric, or generalized, lymphoma is the most commonly reported form and involves multiple peripheral and internal lymph nodes and other organs. The most commonly involved peripheral lymph nodes are the mandibular, caudal cervical, retropharyngeal, and superficial inguinal. The most commonly involved abdominal lymph nodes are the mesenteric, colonic, and deep iliac. Splenomegaly occurs in 25% of the cases, and hepatomegaly or perirenal masses are found infrequently. The multiple sites of involvement probably represent metastasis via the blood and lymphatic circulatory systems. Notably, this is the most common form to be associated with circulating neoplastic lymphocytes, referred to as the “leukemic phase” of lymphoma. Clinical signs reflect dysfunction of affected organs, and the course of the disease is typically rapid once signs become evident.

The alimentary type is the most acute form of lymphoma. It causes rapid deterioration and involves the small intestine and associated mesenteric lymph nodes. Distant metastasis appears slow to develop. Alimentary lymphoma is commonly detected in horses from 2 to 5 years of age. Signs are considered nonspecific and include weight loss, decreased appetite, fever, dependent edema, and diarrhea or abdominal pain of varying severity and duration. Affected horses may have a blunted oral glucose tolerance response and reduced serum albumin concentration, which suggests intestinal malabsorption. Immune-mediated hemolytic anemia and hyperglobulinemia have also been reported to accompany this condition.

Lymphoma of the mediastinal lymph nodes typically occurs in adult horses. The most common clinical signs are referable to compression of intrathoracic structures and include pleural effusion, tachypnea, dyspnea, and dependent edema. Less common findings include a persistent cough, tachycardia, jugular vein distention, and forelimb lameness. Neoplastic cells may be observed in the pleural fluid and the paraneoplastic syndrome of hypercalcemia has been associated with this form of lymphoma.

The most common extranodal sites of tumor development are — in descending order — the skin, upper respiratory tract, eyes or adnexa, and central nervous system. Lymphoma of the skin — the cutaneous form — is the least common form of lymphoma in horses, although it represented the most common form in one report. Tumors are readily identified as nonpainful, dermal, or subdermal masses that are firm and well circumscribed and may be haired, nonhaired, or ulcerated. Horses may have a solitary mass or multiple masses that range in size from a few millimeters up to several centimeters in diameter. The most commonly affected regions include the shoulder, perineum, axilla, and trunk. Clinical signs are referable to internal metastasis and may not be present during the initial examination. Tumors may develop rapidly or slowly and may spontaneously regress and reappear. However, cutaneous lymphoma generally manifests as a slowly progressive extension of an internal malignancy and involves multiple or single, nonulcerated dermal or subdermal masses of neoplastic lymphocytes (i.e., a sarcomatous form). The most rare form of cutaneous lymphoma is termed mycosis fungoides, which differs from the sarcomatous form in that it represents a diffuse infiltration with neoplastic lymphocytes of the dermis or subdermis. This rare form of cutaneous lymphoma is also chronic and progressive and, without appropriate histologic examination of the skin, may be easily mistaken for other diffuse non-neoplastic dermatoses.

Extranodal lymphoma of the eye or adnexa most commonly involves the palpebral conjunctiva and eyelids and may be associated with exophthalmus, exposure keratitis, uveitis, chemosis, and conjunctivitis. Lymphoma has been occasionally reported to involve the upper respiratory tract, thus causing signs of upper airway obstruction with and without nasal discharge. A single recent report involved tumor infiltration of the tongue. Reports of peripheral nerve sheath and epidural infiltration also exist and may be considered rare differentials for lameness and ataxia, respectively. Metastatic periarticular involvement that causes lameness has also recently been reported.

Diagnosis of Lymphoma

Diagnosis of lymphoma can be difficult, and ante mortem confirmation occurs in less than 60% of cases. The key to ante mortem diagnosis is a persistent diagnostician. Neoplasia must always be considered in an adult horse with recurrent inflammatory and febrile episodes that are unresponsive to antimicrobial therapy. The physical examination should include transrectal abdominal palpation and careful thoracic auscultation and percussion. However, the definitive diagnosis of lymphoma requires the observation of neoplastic cells in aspirates or biopsy specimens of lymph nodes and other masses or in centesis samples of body cavity fluids, bone marrow aspirates, or peripheral blood.

Cytologic observations consistent with neoplastic transformation of lymphoid cells include mitotic figures, prominent nucleoli, and binucleation, but evaluation of tissue architecture is equally important in the detection of neoplastic transformation and can only be obtained with biopsy. The observation of neoplastic lymphocytes in the peripheral blood is uncommon and may be a late manifestation of lymphoma in the horse, thus indicating dissemination and bone marrow involvement. When neoplastic cells are observed in the peripheral blood, the leukemia is characterized as subleukemic or leukemic if the total white blood cell count is normal or increased, respectively. Lymphoma is aleukemic when neoplastic cells are not present in peripheral blood. Furthermore, the leukemia may be characterized by the appearance of the transformed cells: acute or lymphoblastic leukemia if immature; chronic or lymphocytic leukemia if mature.

Since publication of the last edition of this text, significant strides have been made in classifying lymphomas using antibodies to cell surface antigens (). Probably the greatest anticipated utility of immunophenotyping equine lymphomas is in the prognostication and choice of anti-neoplastic agent(s), as has been realized in human and small animal veterinary medicine. In addition, immunophenotyping should aid in determining the cell lineage of more poorly differentiated equine tumors, in the correct classification as T cell versus B cell lymphomas, in recognizing phenotypic-specific distri-bution patterns, and in determining the apparent proliferation rates of lymphoid tumors. For example, immunophenotyping has lead to the discovery of a previously unrecognized form of equine lymphoma — the T cell-rich, B cell lymphoma, a form that appears to be prone to subcutaneous tumors. This phe-notype may be a major form of lymphoma in horses and represents 11 out of 24 (or 46%) B cell lymphoma cases and about 33% of all lymphomas.

Paraneoplastic syndromes are the indirect systemic effects of cancer and may have profound consequences on disease expression. The cause of these syndromes is often unknown but generally thought to be mediated by soluble substances released from the neoplastic cells. A few of the paraneoplastic syndromes that may be relevant to horse cancer patients include cachexia, hypercalcemia, hypoglycemia, hypertrophic osteopathy, anemia, disseminated intravascular coagulation, leukocytosis, hyperproteinemia, fever, and various neurologic abnormalities. Adjunct therapy aimed at diminishing paraneoplastic syndromes may have a profound effect on patient comfort and clinical course ().

Anemia is a common finding and occurs in 30% to 50% of horses with lymphoma. Typically, the anemia is mild, normochromic, and normocytic and reflects bone marrow suppression. Immune-mediated hemolytic anemia may be suspected based on a positive direct Coombs’ test. Thrombocytopenia can be profound and has resulted in bleeding diathesis. The number of leukocytes and lymphocytes in the peripheral blood is often within normal limits. With leukocytosis, mature neutrophilia and increased serum fibrinogen activity are most commonly observed and indicate the presence of inflammation. Leukopenia and pancytopenia are uncommon findings.

Common alterations of plasma proteins include increased fibrinogen, total protein, and globulin concentrations. Gammopathy may reflect chronic inflammation but may also reflect neoplastic clonal expansion of B cell lymphocytes (see later section on plasma cell myeloma). Hypoalbuminemia may occur in response to a profound gammopathy or from gastrointestinal loss and rarely from end-stage liver failure as a consequence of hepatic involvement. Both selective (immunoglobulin M [IgM]) and generalized immunoglobulin deficiencies have been occasionally associated with lymphoid neoplasia in horses. Biochemical alterations that may be seen include hypercalcemia, increased liver enzyme activity, and azotemia.

Prognosis and Treatment of Lymphoma

In the majority of patients, rapid deterioration follows the onset of clinical signs associated with internal disease. Horses with lymphoma limited to cutaneous involvement, however, have survived for several years with and without chemotherapeutic intervention. Immunosuppressive glucocorticoid therapy (0.02-0.2 mg/kg dexamethasone [Azium] IV, IM, or PO q24h) may be palliative for steroid-responsive malignancies and may also suppress immune-mediated sequelae, including hemolytic anemia and thrombocytopenia. Cutaneous lesions may regress in 2 to 6 weeks, at which time the dose may be gradually reduced. If glucocorticoid administration is tapered too quickly or is discontinued, more aggressive lymphoid tumors may reappear. Signs of acute laminitis have been observed during glucocorticoid therapy in equine cancer patients and were the grounds for discontinuing therapy.

Few reports discuss use of a specific antineoplastic agent in the treatment of equine lymphoma. The expense and possible toxicity of chemotherapy in the horse are the most common reasons cited for nontreatment. However, the use of a multiple-agent induction protocol in horses with lymphoma has been reported () and is summarized here. Cytosine arabinoside (Cytosar-U; 200-300 mg/m2 SQ or IM) is given once every 1 or 2 weeks. Chlorambucil (Leukeran; 20 mg/m2 PO) is given once every 2 weeks. Prednisone (Deltasone; 1.1-2.2 mg/kg PO) is given every other day throughout the treatment period. Alternatively, cyclophosphamide (Cytoxan; 200 mg/m2 IV given once every 2-3 weeks) is substituted for chlorambucil. Antineoplastic agents are given on alternating weeks but have been given on the same day without apparent consequence. Response to induction therapy should occur within 2 to 4 weeks, but if a response is not observed, adding vincristine (Oncovin; 0.5 mg/m2 IV once a week) to the induction protocol has been recommended.

With remission, the induction protocol is used for a total of 2 to 3 months and then is switched to a maintenance protocol. The first cycle of maintenance therapy increases the treatment interval for each antineoplastic agent by one week; prednisone, however, is given for the duration of therapy and is gradually reduced in dose. After 2 to 3 months on the first cycle, if the horse is still in remission, the second cycle is begun, adding one more week to the treatment intervals of each agent. Several cycles of maintenance therapy can be given; however, most horses in remission are treated for a total of 6 to 8 months.

Other reported protocols include single-agent use of l-asparaginase (Elspar; 10,000-40,000 IU/m2 IM once every 2-3 weeks) or cyclophosphamide (as described previously) and combinations of either cytosine arabinoside or cyclophosphamide with prednisone.

Unfortunately, the likelihood that remission rates and survival times for specific chemotherapeutic protocols and well characterized lymphoid neoplasms in horses (based on a suitably large number of cases) will soon be available is not high. Nevertheless, anecdotal reports suggest remission is possible in some cases of equine lymphoma.

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Horses

Treatment of Cutaneous Lymphosarcoma

Glucocorticoids remain the mainstay of treatment of cutaneous T cell-rich, B cell lymphoma. Tumor regression is typically noted following the systemic administration of dexamethasone (0.02-0.2 mg/kg IV, IM or PO q24h) or prednisolone (1-2 mg/kg PO q24h). In these authors’ experience, dexamethasone proves more effective than prednisolone in treating lymphosarcoma. Once cutaneous lesions have regressed in size and number, the glucocorticosteroid dose can be gradually tapered. However, a rapid decrease or discontinuation of glucocorticosteroid administration may result in recurrence of cutaneous lesions. Relapses are anecdotally reported to be sometimes more refractory to treatment. Long-term maintenance therapy may be required in these cases. These authors prefer to use a dose of 0.04 mg/kg of dexamethasone (approximately 20 mg for an average-size horse) once daily until significant regression of tumors has occurred; the dose then is reduced to 0.02 mg/kg daily and then to every 48 hours. Intralesional injections of betamethasone or triamcinolone can also be performed with success; this may be impractical when presented with a large number of cutaneous lesions. Topical application of corticosteroid preparations may result in clinical improvement in cases with ulceration; however, results of its use have not been reported. In addition to im-munosuppression, laminitis is a potential side effect of corticosteroid administration.

Exogenous progestins may demonstrate an antiproliferative effect on lymphosarcoma tumors. The exact mechanism of action has not been determined; however, it is believed to be due to the presence of progesterone receptors, which have been demonstrated on both neoplastic and normal equine lymphoid tissues. Progestogens also have glucocorticoid-like activity, which may also account for the response observed in some cases of lymphosarcoma. In one study, progesterone receptors were identified on 67% of the subcutaneous lymphosarcoma tumors that were evaluated (primarily representing T cell-rich, B cell tumors). In the mare diagnosed with simultaneous cutaneous histiolymphocytic lymphosarcoma and a granulosatheca cell ovarian tumor, partial regression of the skin lesions occurred following a ten-day course of the synthetic progestin, altrenogest (0.044 mg/kg q24h PO). A temporary response was also observed after unilateral ovariectomy. The ovarian tumor stained positive for estradiol and led the authors to believe it was estrogen-secreting. The authors speculated that the steroid hormones secreted by the ovarian tumor may have influenced growth of the T cell-rich, B cell tumors by leading to low progesterone concentrations. Anecdotal reports of tumor regression during pregnancy also exist. In one mare with cutaneous T cell lymphosarcoma, regression of nodules was noted after surgical excision, a single intralesional injection of betamethasone (0.04 mg/kg), and an 8-day course of the oral progestogen, megestrol acetate (0.2 mg/kg q24h). Surgical excision may be efficacious in cases in which a single or a small number of cutaneous nodules exists.

The administration of autologous tumor cell vaccines may benefit horses with cutaneous lymphosarcoma. In one report, tumor regression was achieved by using a combination of low-dose cyclophosphamide and autologous tumor cells infected with vaccinia virus. Cyclophosphamide is thought to potentiate the immune response by decreasing suppressor T cell activity. Infection of tumor cells with the vaccinia virus was performed to augment the host antitumor immune response. The treatment protocol included intravenous administration of cyclophosphamide (300 mg/m2) via a jugular catheter over a period of 2 to 3 minutes on days 1 and 36. Immunization with tumor-cell vaccine was performed on days 4 and 21. Response to immunostimulation was confirmed by development of a delayed-type hypersensitivity response to autologous tumor cells injected intradermally in the horse. Potential side effects of cyclophosphamide administration in other species include immunosuppression, enterocolitis, myelosuppression, and hemorrhagic cystitis. No side effects were noted in the horse in this report.

Treatment of epitheliotropic (cutaneous T cell lymphosarcoma) in horses remains speculative because of a paucity of reported cases. Surgical excision of small lesions may be curative. Retinoids and vitamin A analogs inhibit malignant lymphocyte proliferation in human and canine patients with epitheliotropic lymphosarcoma. No reports of the use of retinoids in horses have been published. However, these authors noted no gross or histologic improvement in treating one case of equine epitheliotropic lymphosarcoma with retinoid cream. Side effects included local erythema and signs of irritation after repeated applications.

Investigations as to the effectiveness of radiation therapy and systemic chemotherapy in the management of equine cutaneous lymphosarcoma are needed. Local therapy that consists of intralesional injection of cutaneous nodules with cisplatin has been used successfully in horses with a small number of lesions. Combination chemotherapy that consists of cytosine arabinoside, chlorambucil or cyclophosphamide, prednisone, and vincristine has been reported for use in horses with multicentric lymphosarcoma, as has L-asparaginase.

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Veterinary Drugs

Cytarabine

Chemistry

A synthetic pyrimidine nucleoside antimetabolite, cytarabine occurs as an odorless, white to off-white, crystalline powder with a pKa of 4.35. It is freely soluble in water and slightly soluble in alcohol. Cytarabine is also commonly known as ARA-C or Cytosine Arabinoside. It may also be known as 1-beta-D-Arabinofuranosylcytosine or Arabinosylcytosine.

Storage – Stability – Compatibility

Cytarabine sterile powder for injection should be stored at room temperature (15-30°C). After reconstituting with bacteriostatic water for injection, solutions are stable for at least 48 hours when stored at room temperature. One study however, demonstrated that the reconstituted solution retains 90% of its potency for up to 17 days when stored at room temperature. If the solution develops a slight haze, the drug should be discarded.

Cytarabine is reportedly compatible with the following intravenous solutions and drugs: amino acids 4.25%/dextrose 25%, dextrose containing solutions, dextrose-saline combinations, dextrose-lactated Ringer’s injection combinations, Ringer’s injection, lactated Ringer’s injection, sodium chloride 0.9%, sodium lactate 1/6 M, corticotropin, lincomycin HCl, methotrexate sodium, metoclopramide HCl, potassium chloride, prednisolone sodium phosphate, sodium bicarbonate, and vincristine sulfate.

Cytarabine compatibility information conflicts or is dependent on diluent or concentration factors with the following drugs or solutions: cephalothin sodium, gentamicin sulfate, hydrocortisone sodium succinate, and methylprednisolone sodium succinate. Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used. It is suggested to consult specialized references for more specific information (e.g., Handbook on Injectable Drugs by Trissel).

Cytarabine is reportedly incompatible with the following solutions or drugs: carbenicillin disodium, fluorouracil, regular insulin, nafcillin sodium, oxacillin sodium, and penicillin G sodium.

Pharmacology

Cytarabine is converted intracellularly into cytarabine triphosphate which apparently competes with deoxycytidine triphosphate, thereby inhibiting DNA polymerase with resulting inhibition of DNA synthesis. Cytarabine is cell phase specific, and acts principally during the S-phase (DNA synthesis). It may also, under certain conditions, block cells from the G1 phase to the S phase.

Uses – Indications

In veterinary medicine, cytarabine is used primarily in small animals as an antineoplastic agent for lymphoreticular neoplasms, myeloproliferative disease and CNS lymphoma. Refer to the Dosages below or the Protocols (at the end of this section), for more information.

Pharmacokinetics

Cytarabine has very poor systemic availability after oral administration and is only used parenterally. Following IM or SQ injections, the drug peaks in the plasma within 20-60 minutes, but levels attained are much lower than with an equivalent IV dose.

Cytarabine is distributed widely throughout the body, but crosses into the CNS in only a limited manner. If given via continuous IV infusion, CSF levels are higher than with IV bolus injection and can reach 40-60% of those levels found in the plasma. In humans, cytarabine is only about 13% bound to plasma proteins. The drug apparently crosses the placenta, but it is not known if it enters milk.

Circulating cytarabine is rapidly metabolized by the enzyme cytidine deaminase, principally in the liver, but also in the kidneys, intestinal mucosa, and granulocytes, to the inactive metabolite ara-U (uracil arabinoside). About 80% of a dose is excreted in the urine within 24 hours as both ara-U (~90%) and unchanged cytarabine (~10%).

Contraindications – Precautions – Reproductive Safety

Cytarabine is contraindicated in patients hypersensitive to it. Because of the potential for development of serious adverse reactions, cytarabine should only be used in patients who can be adequately and regularly monitored.

The person preparing or administering cytarabine for injection, need not observe any special handling precautions other than wearing gloves. However, should any contamination occur, thoroughly wash off the drug from skin or mucous membranes.

Cytarabine’s safe use in pregnancy has not been established and it is potentially teratogenic and embryotoxic.

Adverse Effects – Warnings

The principal adverse effects of cytarabine is myelosuppression (with leukopenia being most prevalent), but anemia and thrombocytopenia can also be seen. Myelosuppressive effects are more pronounced with IV administration and reach a nadir at 5-7 days, and generally recover at 7-14 days.

Gi disturbances (anorexia, nausea, vomiting, diarrhea), conjunctivitis, oral ulceration, hepatotoxicity and fever may also be noted with cytarabine therapy. Anaphylaxis has been reported, but is believed to occur very rarely.

Cytarabine is a mutagenic and potentially carcinogenic agent.

Overdosage – Acute Toxicity

Cytarabine efficacy and toxicity (see Adverse Effects) are dependent not only on the dose, but also the rate the drug is given. In dogs, the IV LD50 is 384 mg/kg when given over 12 hours and 48 mg/kg when infused IV over 120 hours. Should an inadvertent overdose occur, supportive therapy should be instituted.

Drug Interactions

Presumably due to causing alterations in the intestinal mucosa, cytarabine may decrease the amount of digoxin (tablets only) that is absorbed after oral dosing. This effect may persist for several days after cytarabine has been discontinued.

Limited studies have indicated that cytarabine may antagonize the anti-infective activity of gentamicin or flucytosine. Animals receiving either of these drugs with cytarabine should be closely monitored for decreased anti-infective efficacy. Drug/Laboratory Interactions

None reported.

Doses

For more information, refer to the protocol references found in the appendix or other protocols found in numerous references, including: Handbook of Small Animal Practice; Handbook of Small Animal Therapeutics; and Textbook of Veterinary Internal Medicine, 3rd Edition.

Doses for dogs:

For susceptible neoplastic diseases:

a) 100 mg/m2 IV or SQ once daily for 2-4 days; repeat prn 20 mg/m2 intrathecally for 1-5 days.

b) 100 mg/m2 IV (slowly), IM, or SQ once daily for 4 days, if no toxicity develops may increase dose by 50%.

Doses for cats:

For susceptible neoplastic diseases:

a) 100 mg/m2 IV or SQ once daily for 2-4 days; repeat prn 20 mg/m2 intrathecally for 1-5 days.

b) 100 mg/m2 once daily for 2 days; 10 mg/m2 once daily for 2 weeks.

Monitoring Parameters

1) Efficacy; see the Protocol section or refer to the references from the Dosage section above for more information.

2) Toxicity; see Adverse Effects above. Regular hemograms are mandatory. Periodic liver and kidney function tests are suggested.

Client Information

Clients must be briefed on the possibilities of severe toxicity developing from this drug, including drug-related mortality. Clients should contact the veterinarian should the patient exhibit any symptoms of profound depression, abnormal bleeding and/or bruising.

Dosage Forms – Preparations – FDA Approval Status – Withholding Times

Veterinary-Approved Products:

None

Human-Approved Products:

Cytarabine Powder for Injection 100 mg, 500 mg, 1 g & 2 g in vials; Cytosar-U® (Upjohn) (Rx); generic (Rx)

Cytarabine Injection 20 mg/ml in 5 ml vials and 50 ml bulk vials; Tarabine PRS® (Adria) (Rx)