----start----- medsurg2 9/14 Dr Barber Canine and feline leukemias leukemia == glamour disease in human medicine (?) b/c it strikes younger people as well as older, and doesn't cause big tumor masses, or disfigurement. also there are a lot of high tech txs to apply to them like BM transplant, monitoring with PCR for molecular remissions, etc. so it's dramatic and exciting, and curable too. unfortunately, it's not the same in our pets. it's very rare, and usually not curable. also, there are some misconceptions. people think of cancer as one disease. then, also, they think of leukemia as one disease. really they are several disaeses, of the bone marrow. Leukemia == neoplastic disease of the bone marrow in which > 30% of nucleated cells are abnormal. origin is a hematopoietic cell that has undergone malignant transformation and then clonal expansion and proliferation. aleukemic - no malignant cells in peripheral blood subleukemic - a smattering of malignant cells in blood with normal blood counts leukemic - most of the nucleated cells in the blood are malignant myelodysplasia - maturation defect in one or more heamtopoietic lines; < 30% of nucleated cells affected. this is an umbrella term for a bunch of disorders, many of which are "pre-leukemic" to differentiate - when you think you have a leukemia, is it truly neoplastic, or is it reactive? Reactive response == leukemoid reaction == high numbers of nucleated cells in the periphery that are normal cells there reacting to something - leukemoid reaction may be seen with closed pyometra, for example. also if you have a septic response,where you use up all the peripheral PMNs, and the BM is all cranked up - this can still be a leukemoid response - when there are no mature nucleated cells in the periphery, but some immature ones. need BM biopsy to sort this out. myelophthisis - crowding out of bone marrow by neoplastic cells. when BM is full of neoplastic cells, normal stem cells are crowded out. if there is fibrosis or scarring in BM, it's called myelofibrosis - have to look at BM to tell these apart. so an owner may ask "how did my pet get this"? the answer is "we do not know" especially if it is a dog. etiology: generally unknown virus - in the cat, FeLV is one cause - strongly associated with lymphoproliferative disorders such as leukemia or lymphoma. Also HIV infected people in japan chemical (benzene or chemotherapeutic alkylating agent) or physical (radiation - low risk with therapeutic dose; high risk with atomic bomb exposure) agents genetic alterations (Philadelphia chromosome with CML in people, Downs syndrome) immune dysfunction (predisposes people and animals to cancers) (HIV, FIV) classification: acute vs chronic - per cell morphology, not clinical distinction lymphoproliferative vs myeloproliferative - per cell of origin acute: immature blast cells. very severe signs, shorter course. duration and severity of signs usually correlate with degree of cell maturity chronic: mature cells - less severe signs - some chronic leukemias are actually found as incidental findings on routine bloodwork! nomenclature: acute ___blastic; chronic ___cytic lymphoproliferative: restricted to lymphoid series myeloproliferative: monocytic, granulocytic, erythrocytic, megakaryocytic when you say myeloproliferative, people usually think monocytic or granulocytic, so some people say non-lymphoid instead of myeloproliferative acute undifferentiated leukemia: pluripotential stem cell acute lymphoblastic leukemia, chronic lymphocytic leukemia and multiple myeloma - lymphoid stem cell origin acute megakaryocytic leukemia, essential thrombocytopenia - megakaryoblastic origin polycythemia rubra vera and erythemic myelosis - rubriblast origin acute myelogenous leukemia and eosiniphilic and basophilic leukemia - myeloblast origin acute monocytic and chronic monocytic leukemias - monoblast origin acute myelomonocytic and chronic myelomonocytic and erythroleukemia - erythroblastic origin incidence: dogs: lymphoid leukemia most common (although this isn't certain as we do not have good reporting and leukemias are really really rare). but we have a lot of informatoin about lymphosarcomas - risk 13-24/100,000/yr. probably 1/10 that for leukemias. ALL and CLL - acute more common cats: bone marrow disease is more common - about 200/100,000/yr. lymphoproliferative disease most common. acute also more common. clinical signs: all of these signs occur with chronic or acute leukemias, but are more severe with acute leukemias pallor - anemia: common, nonregenerative (normocytic, normochromic). causes: myelophthisis, hemorrhage, "anemia of chronic disease." Also, degree of anemia isn't usually correlated with abnormal cells...it's likely the neoplastic cells elaborate some factor that suppresses normal hematopoiesis hemorrhage/bruising: causes: thrombocytopenia due to myelophthisis or hyperviscosity syndrome, decreased clotting factors due to hepatic infiltration (rare, terminal), or DIC (very common cause of death with acute leukemias) infection: very common; due to neutropenia due to myelophthisis or impaired neutrophil function due to factors secreted by malignant cells; common cause of death in these animals ocular changes: owner may see theses first: retinal hemorrhage, detachment, hyphema, glaucoma, chmosis, conjunctivitis, chorioretinitis. more common with nonlymphoid leukemias. prevalence of this problem - up to 30% of animals with nonlymphoid leukemias. fever: caused by infection or paraneoplastic syndrome (pyrogen release or IL1, IL6, TNF elaborated by leukemic cells) neurological signs: due to neoplastic infiltration around CN, meninges; or due to bleeding into subarachnoid space, or hyperviscosity syndrome. may see cranial nerve signs, head tilts, facial paralysis, etc; disorientation or dementia; incoordination; seizures; vomiting. organomegaly: hepatomegaly, splenomegaly (most common- due to infiltration, extramedullary hematopoiesis), renomegaly (uncommon, more often in cats), lymphadenopathy (very common with leukemias but usually mild to moderate- if huge LNs, think LSA - but you treat ALL similarly to LSA) nonspecific/constitutional unfortunately, the nonspecific signs are most common: lethargy, weakness, weight loss, inappetance Diagnosis: CBC: look for increased # immature cells - or increased numbers of normal cells. look at morphology - blastic or mature. also look for cytopenias - only one cell line may be involved; or pancytopenia is possible. also - platelet and retic counts should be done to determie if you have regenerative or nonregenerative anemia (with leukemia, tends to be nonregenerative) and special stains will be needed if you have undifferentiated cells present. slide: HCT tube with blood from AML patient - we see three stripes - the red cell layer, a white cell layer, and a pink plasma layer. these are all the same size, so that is a big buffy coat - >700,000 WBC. slide: blood smear showing vastly increased numbers of lymphocytes - CLL with pretty normal looking lymphocytes. slide: AML - these cells are much bigger than RBCs - this is a non lymphoid, blastic leukemia (although the malignant cells look to me like lymphocytes or plasma cells) BM aspirate +/- core biopsy: this will give the definitive diagnosis. even if you see malignant cells in the periphery you should do this, b/c it can let you know how much of the BM is infiltrated, so you can assess the prognosis. you can see what reserves are there, if there are maturation arrests, whatever. special stains may be needed. aspirate is easier to do than core biopsy, but may not be diagnostic. serum biochemistry - check for organ involvement - kidney, liver - these tend to be terminal events, indicate advanced disease; also paraneoplastic syndromes exist - hypercalcemia, macroglubulinemia esp with ALL (IgM); also rule out intercurrent disease, differentiate b/w liver infiltration and other liver dz! FeLV test - cat. do ELISA on peripheral blood.if it is negative, though, do a BM IFA when you do a marrow aspirate. some cats will be ELISA neg in periphery but IFA + in BM during earlier phases of disease. special tests to determine cell type: acute lymphoid vs nonlymphoid disease, immunohistochemistry, flow cytometry (B v T lymphocytes). lymphoid leukemias are more treatable; nonlymphoid disease is less amenable to chemotherapy. it may not be useful to differentiate between the possible nonlymphoid leukemias, b/c we don't have treatments for them anyway. special stains - have not been listed in handout, you don't have to know it, but you can ask her about it if you are interested. other: tick titers, look for pyometra or other source of inflammation, ANA to look for other immune mediated dz... Prognosis: acute: guarded to grave lymphoid: guarded- median survival 4 mos w/tx (dog and cat) nonlymphoid: poor to grave - survival days/weeks w/or w/o tx (dog) cats usually euthanized at time of dx, usually really sick chronic: fair to good lymphoid: fair to good - survival up to 3+ yrs with tx nonlymphoid: fair to good - survival can exceed 1 yr w/tx (dogs), no cat data available (not reported in cats) Treatment: what can we do, when and how, and should we? 1. supportive care - important for managing complications such as sepsis, bleeding, etc. 2. chemotherapy 3. radiation 4. BMT treatment goals: acute leukemia - obliterate the neoplastic clone, eradicate it from the BM, allow repopulation of normal marrow tx goals, chronic leukemia: suppress excessive rate of hematopoiesis. usually we use chemotherapy for both. acute: aggressive protocols using IV drugs that are pretty toxic. lymphoid - tx similar to lymphoma - see handout for protocols; nonlymphoid - no standard protocols exist. the idea is, we're treating cells with high growth fraction, so they are responsive. because it is rapidly progressive, you have to treat immediately. in humans, often ablate BM with chemo at high doses and/or radiation, and then give BM transplant and/or component transfusions. intense process with high morbidity/mortality. Our patients can't give consent to this, and there is debate about whether it is ok to do this. most have elected to put quality of life above quantity, and to withhold this very toxic treatment. so we do not do BMT, we do not cure as many animals. chronic: slow alkylating agents - often oral meds. more of these cells are resting in Go - tx as for acute disease not rewarding since cells are less responsive, so we use the alkylating agents. in humans, tx of chronic leukemias is thought to decrease morbidity without decreasing mortality. in veterinary oncology, we think we do increase survival by allowing normal hematopoiesis to occur. it does depend when you decide to start tx, though. when dx incidentally, we often just monitor until animal shows clinical signs, or neoplastic cell population hits a certain number...then treat. [she's gone 5 min over her time....sigh] supportive care: transfusion, broad spectrum abx for sepsis from disease or chemo, colony stimulating factors to increase cell lines (normal cell lines) (controversial b/c some of these factors may stimulate the cancer, plus recombinant human products may induce antibody formation), plasmapheresis to tx hyperviscosity, nutritional support. radiation therapy: to ablate BM in humans, or to pre-treat the CNS which is a sanctuary site for leukemias since drugs do not cross BBB. people tend to relapse within CNS. radiation therapy not routinely done in veterinary medicine, though some places do use it. BMT: investigational, rarely used biologic response modifiers: investigational agents: antiangiogenic drugs, cell cycle inhibitors, protease inhibitors, immunomodulatory drugs take home points: leukemia is a bone marrow dz two major types: acute v chronic, based on cell morphology also lymphoid v nonlymphoid often need special stains to tell apart acute leukemias type has major impact on tx and prognosis chemo is standard tx ----end----