6 yr old MC labrador retriever. Peripheral Neutropenia and Occult Lymphoproliferative Disorders. 6 yr old MC labrador retriever.

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1 Peripheral Neutropenia and Occult Lymphoproliferative Disorders Paul R. Avery VMD, PhD, DACVP Melanie S. Spoor Laurie Bohannon-Worsley Lauren C. Taraba Matthew D. Jones Anne C. Avery VMD, PhD Colorado State University 6 yr old MC labrador retriever Acute onset lethargy/anorexia PE unremarkable NUCLEATED CELLS x 10^3/ul BAND NEUTROPHILS x 10^3/ul SEG NEUTROPHILS x 10^3/ul LYMPHOCYTES x 10^3/ul MONOCYTES x 10^3/ul PLASMA PROTEIN g/dl RBC x 10^6/ul PCV % RETICULOCYTES 50, #/ul PLATELETS x 10^3/ul 6 yr old MC labrador retriever Total calcium: 15.7 mg/dl ( mg/dl) Ionized calcium: 1.68 mm/l ( mm/l) PTH: 1.5 pmol/l (2-13 pmol/l) Normal LN aspirate: Reactive Splenic aspirate: Extramedullary hematopoiesis SPE: wnl Thoracic/Abd rads: mild splenomegaly : : -Myeloid Hyperplasia w/ maturation arrest -Megakaryocytic hyperplasia Immune-mediated vs. Inflammatory consumption 1

2 6 yr old MC labrador retriever Started on immunosuppressive steroids Day 0 Day 2 Day 7 Neutrophils: Platelets: 29,000 83, ,000 Gradually Tapered down to 10mg pred SID over 4 month period 6 months later: Lethargy, melena Platelets: 22,000, PCV: 20%, Neuts: 2,800 Calcium wnl Submandibular LNs slightly enlarged Mild splenomegaly, enlarged abd LNs Bone marrow aspirate: Immunohistochemistry 40x 10x Lymphoma Control Immunohistochemistry Lymph Node Are some cases of immune-mediated neutropenia associated with indolent lymphoproliferative disease? Patient 2

3 Human LGL Leukemia LGL counts may be low or high May be difficult to find in the marrow Diffuse infiltration Recurrent cytopenias can precede increases in detectable by up to 6 yrs Clinical course may be prolonged (several years) but appears to be ultimately fatal Manifestation of human LGL leukemia Anemia Syndrome 27 PATIENTS % of patients affected 44 9 yr old FS Dog: CBC Thrombocytopenia Rheumatoid arthritis Death due to infection ANA Anti-neutrophil neutrophil antibodies Gentile et al, Leuk lymph 1996;23:365 9 yr old FS dog (cont.): -ANA + at 1:100 -PCR on bone marrow: + for clonality + ctrl Prednisone 24 hrs 3

4 4 days after starting prednisone: 9 yr old FS dog (cont.): -Clinically, dog still lethargic/adr -began tx for lymphoma -stopped after 1x l-aspar, 2x vincristine, prednisone -Dog euthanized 8 months later for progressive neurologic dz. -Necropsy: Glioma, liver/spleen/lns grossly wnl - Excess lymphocytes in marrow - positive by IHC 8 yr old FS Rottweiler: 12/03: Neutropenic, diarrhea, fever Aspirate: Myeloid hyperplasia; L shift 27% large granular lymphs PCR positive- Responded to steroids -couldn t wean below 20 mg SID 8 yr old FS Rottweiler: Large Granular Lymphocytes 8/04: Neutropenic (0 neutrophils seen), diarrhea, fever Aspirate: Myeloid hyperplasia; L shift No lymphocytes seen PCR positive- Neutrophil numbers increased on steroids Euthanized-no necropsy PARR on : 12/03 Patient A=DNA standard B= I C= II D= dog A B C D A B C D 8/04 A B C D Neutropenia Study Group Absolute neutropenia at presentation VTH CSU No recent history of antimicrobials, anticonvulsants or chemotherapeutic drugs No obvious source of intense inflammation No clinical suspicion for parvovirus infection 4

5 Neutropenia Study Group 11 dogs met inclusion/exclusion criteria 2 mixed breed, 2 Rottweilers, Collie, Schnauzer, Lab, Golden Retriever, Australian Shepherd, Cocker Spaniel, Wheaten Terrier 7 spayed females, 4 castrated males Age: mean=5.25 yrs, median=6 yrs (range 2-8) PCR for lymphocyte clonality, long term follow-up data Summary Data: 4 yr old FS Collie 2 yr old FS Mix 8 yr old FS Rott 6 yr old FS Mix 5 yr old Schnauzer 4 yr old MC Cocker Span 7 yr old MC Rott 6.5 yr old FS Aus Shep 6 yr old MC SCWT 3 yr old FS GR 6 yr old MC Lab Neut # 700/uL 0/uL 500/uL 800/uL 200/uL 1,400/uL 100/uL 100/uL 700/uL 1,100/uL 200/uL MHypo, MA,,, sl incr plasma cells Mhypo, MA, Pred Response No ND ND PCR Clonality Outcome LTFU LTFU Euthanized-no necropsy Euthanized-increased s in BM Euth-atypical plasma cells in focal bone lesion Euth- lymphoma Euth-mediastinal/liver masses, Asp=lymphoma Alive and well 2 yrs later Euthanized-plasmacytosis in BM Alive and well 3 yrs later Euth- lymphoma MH=Myeloid hyperplasia, Mhypo=Myeloid hypoplasia, MA=Maturation arrest 5