Introduction

Leukemia is a term used to describe the presence of neoplastic hematopoietic cells in peripheral blood or bone marrow which originate from bone marrow or, in some cases, the spleen. It originates from the Greek "leukos" (white) plus "haima" (blood), which refers to the increased buffy coat layer seen in some cases of leukemia. Some neoplastic disorders, like multiple myeloma and histiocytic sarcoma are not considered leukemias besides their bone marrow involvement. Leukemia represents less than 10% of hematopoietic neoplasias in dogs and around 15-35% in cats. Besides FeLV infection in cats, there is not any other proven etiology for leukemia in small animals.

Classification

Criteria for the classification of leukemia include the presence of neoplastic cells in blood, the clinical course and cell differentiation and lineage (Table 1). In aleukemic leukemias, neoplastic cells are not observed on blood films, representing around 10% of the cases of leukemia. In patients with subleukemic leukemia they may be present in low numbers. This makes the presence of any number of atypical cells, particularly if accompanied by cytopenias, an indication for bone marrow, spleen or lymph nodes biopsies to search for neoplasia.

Acute leukemias are usually associated with a more aggressive behavior, a short survival time in untreated cases and the involvement of blast cells. Chronic leukemias have a slower progression and the neoplastic cells are more differentiated and usually have a normal appearance.

Cell lineage identification is an important step in the classification of leukemia, once therapeutic protocols will depend on it. Initially, leukemia is classified in lymphoproliferative and myeloid or myeloproliferative disorders, and then in their acute or chronic forms and cell subtypes. Classification schemes for leukemia has been followed human criteria and had been adapted by the Animal Leukemia Study Group of the American Society for Veterinary Clinical Pathology. Acute myeloid leukemias have also been classified according to a French-American-British system. Recent reviews have shown the need for further studies in order to reach adequate criteria for the classification of myeloid neoplasms.

Table 1. Classification of leukemia in animals.

 Lymphoproliferative disorders

 Acute lymphoblastic (lymphocytic) leukemia--ALL Chronic lymphocytic leukemia--CLL

 Myeloid neoplasms

 Acute myeloid leukemias

 Acute myeloblastic leukemia with minimal differentiation--LMA-M0

 Acute myeloblastic leukemia without differentiation--LMA-M1

 Acute myeloblastic leukemia with maturation--LMA-M2

 Acute promyelocytic leukemia--LMA-M3 (not recognized in animals)

 Acute myelomonocytic leukemia--LMA-M4

 Acute monocytic leukemia--LMA-M5

 Acute erythroleukemia--LMA-M6

 Acute erythroleukemia with erythroid predominance--LMA-M6Er

 Megakaryoblastic leukemia--LMA-M7

 Chronic myeloproliferative disorders

 Chronic myeloid leukemia

 Chronic myelomonocytic leukemia

 Chronic monocytic leukemia

 Eosinophilic leukemia

 Basophilic leukemia

 Polycythemia vera

 Essential thrombocythemia

 Myelodysplastic syndromes--MDS

Myelodysplastic syndromes (MDS) are a group of disorders characterized by an ineffective hematopoiesis and dysplastic alterations in single to multiple cell lineages. Besides the increase in the number of blast cells in marrow, MDS does not fulfill the >30% blasts criteria for AML. However it has been considered a preleukemic disorder, since domestic animals with MDS may develop AML. It must be differentiated from other benign forms of dysplasia secondary to some drugs, toxins, inflammatory, infectious and immune-mediated processes, which should resolve with the correction of the primary disease.

Clinical Course and Diagnosis

Clinical signs are usually unspecific. Dogs with chronic leukemias, especially CLL, are often asymptomatic. Some animals may have a history of lethargy, anorexia and weight loss and a mild lymphadenopathy and splenomegaly may be noticed. In acute leukemias, clinical signs are more severe and may include prominent splenomegaly, hepatomegaly, lymphadenopathy, hemorrhages and neurological problems. Fever and cytopenias may also be seen. Systemic involvement, with the concurrent observation of cytopenias and other paraneoplastic syndrome manifestations implies a poorer prognosis to the case.

Identifying leukemia is not usually a challenging diagnosis, since in most cases a huge number of neoplastic cells can be observed in blood films. However, a bone marrow biopsy (core or aspiration) may be necessary in many situations because some animals may not show any alteration in peripheral blood. The presence of 30% or more blast cells in the marrow is diagnostic for acute myeloid leukemia, although this limit is currently under discussion. The importance of examining bone marrow is enforced by the fact that lymphomas, in addition to ALL, may eventually release lymphoblasts into the blood of some animals and that some cases of MDS may also present some blast cells in the peripheral blood.

Morphologic identification of the cell lineage of poorly differentiated leukemias with routine hematologic stains may be very difficult. Special stains (cytochemistry), monoclonal antibodies techniques (immunocytochemistry and flow cytometry) and molecular genetic tests may be necessary to reach a specific diagnosis. CD79a, CD3, CD11b, CD41, CD1c and CD34 are some of the recommended immunophenotyping markers for animal leukemias. Exclusionary tests are used in the differentiation of chronic well-differentiated leukemias from inflammatory or benign reactive conditions. Clonability tests may be necessary in some situations, but they are not yet available for routine use. Once the leukemia has been diagnosed and staged, CBC will be adequate for the following up of the case.

Treatment

Therapy for acute leukemias must be aggressive in order to restore hematopoiesis by the remnant normal hematopoietic cells previously suppressed by the infiltration of bone marrow by malignant cells. Supportive therapy with broad-spectrum antibiotics, fluid therapy, blood components, and nutritional support are sometimes as important as the chemotherapy itself.

An effective protocol has not been established for ALL yet, but CHOP protocols (cyclophosphamide, doxorubicin, vincristine and prednisone) like those used to treat lymphoma has been used in dogs with ALL. Treatment of ALL can be frustrating once complete remission rate is usually much less than 30%. Use of L-asparaginase may increase the response rates.

Treatment of chronic leukemia, especially CLL, is controversial because of its indolent nature. In these cases it is recommended to start chemotherapy if any sign of significant organomegaly, anemia or thrombocytopenia or an excessive leucocyte count is noticed. Chlorambucil is the most effective drug evaluated for the treatment of CLL in dogs and cats. A combined protocol with chlorambucil and prednisone showed a better antitumor activity in humans. Although complete remissions are rare, survival times vary among 1 to 3 years with a good quality of life.

AMLs present a poor response to therapy and due to scarce information on the literature regarding the response of the subtypes of AML, there is no consensus on the protocol to treat these conditions. Cytosine arabinoside in combination with doxorubicin or cyclophosphamide, and vincristine and prednisone are the most common agents used in the treatment of AML. The COAP (cyclophosphamide, vincristine, cytosine arabinoside and prednisone) protocol can be used as maintenance therapy once remission is achieved. Chronic myeloid leukemia, thrombocythemia and polycythemia vera are treated with hydroxyurea. Phlebotomy alone or in combination to chemotherapy can be used in the treatment of polycythemia vera. Despite the response to chemotherapy in CML, many dogs will eventually undergo a terminal phase characterized by a blast crisis.

More detailed protocols and schemes for the treatment of leukemia in dogs and cats can be easily found elsewhere.

Alternatives to the traditional chemotherapy are under investigation and includes radiotherapy, immunotherapy, antiangiogenic drugs and bone marrow transplantation.

Conclusions

The side effects of chemotherapy and its relative effectiveness make the pursuit of a specific diagnosis the first goal in the management of leukemic patients. In general the prognosis for chronic leukemias is better than acute one. Supportive therapy and the following up of clinical signs and the CBC of the patient is important for therapeutic and prognostic purposes. Besides the small remission indexes of some types of leukemia, every effort to maintain the patient's quality of life should be done.

References

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3.  Mcmanus PM. Classification of myeloid neoplasms: a comparative review. Veterinary Clinical Pathology, v.34, n.3, 2005. p.189-212.

4.  Stockham SL, Scott MA. Bone marrow and lymph node. In: Fundamentals of Veterinary Clinical Pathology. Iowa: Blackwell, 2008. P.324-68.

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