Effect of Chemotherapy Schedule on Response in Waldenström's Macroglobulinemia in a Dog

A25.3 kg, 4-year-old spayed female Labrador Retriever was referred to the Purdue University Veterinary Teaching Hospital (PUVTH) emergency service for progressively worsening inappetance, lethargy, polyuria, and polydipsia for a duration of 1 week. Intermittent regurgitation and diarrhea began the day before presentation. The referring veterinarian treated the dog with fluids IV and antibiotics without response. The dog was alert and responsive at presentation. Physical abnormalities included a body condition score of 2/5, pallor, tacky mucous membranes, bilateral enlargement of popliteal and mandibular lymph nodes, splenomegaly, and a grade 2/5 lameness of the right pelvic limb. Body temperature, pulse rate, and respiration rate were normal. A complete blood count (CBC) revealed hyperproteinemia (10.7 g/dL; reference range, 6.0–8.0 g/dL), and a moderate normocytic normochromic anemia (HCT, 26%; reference range, 37–55%). Marked rouleaux, rare immature lymphocytes, and lymphoblasts were apparent on the blood smear. These intermediate-sized plasmacytoid cells had round nuclei with moderately coarse chromatin, occasional small nucleoli, and scant cytoplasm with occasional punctuate vacuoles. The immature lymphocytes suggested the presence of a lymphoid neoplasm. Platelet clumping prevented an automated count, but they appeared decreased on blood smear evaluation. Serum biochemistry revealed mild hypercalcemia (13.0 mg/dL; reference range 9.7–12.3 mg/dL), hypernatremia (153 mg/dL; reference range 138–148 mg/dL), and hyperproteinemia (13.3 g/dL; reference range, 4.8–6.9 g/dL) characterized by hyperglobulinemia (10.9 g/dL; reference range, 1.7–3.8 g/dL). Urinalysis revealed a specific gravity of 1.012 with proteinuria (>1,000 mg/dL). The dog was admitted to the hospital and treated with lactated Ringer's solution and doxycyclinea (5 mg/kg IV q24h). The following day, a CBC revealed persistent hyperproteinemia (10.3 g/dL), a severe nonregenerative anemia (HCT, 18%; reticulocytes, 7,890/μL; < 60,000/μL although this “nonregenerative” refers to the reference range, it is a bit confusing) neutropenia (2,370/μL; reference range, 3,000–12,000/μL), and thrombocytopenia (51,900/μL; reference range 200,000–500,000/μL). Rouleaux formation, immature lymphoid cells, and lymphoblasts were repeatable findings. Serum biochemistry revealed a decreasing hypercalcemia (12.6 mg/dL) and persistent hypernatremia (153 mmol/L). Reductions were noted in hyperproteinemia (12.0 g/dL) and hyperglobulinemia (9.0 g/dL) Thoracic radiographs showed diffuse interstitial pulmonary infiltrates throughout all lung fields. Abdominal radiographs showed marked splenomegaly and remodeling of the right femoral head and neck, consistent with arthritis. Abdominal ultrasonography revealed an enlarged spleen with a coarse echotexture, and multiple enlarged mesenteric lymph nodes. Fundoscopic examination revealed tortuous vessels with retinal hemorrhages bilaterally, and evidence of retinal detachment in the right eye. Aspiration cytology of the popliteal lymph node revealed a heterogeneous lymphoid cell population of predominantly small mature lymphocytes, followed by increased numbers of mature plasma cells, intermediate lymphocytes, and large lymphoblasts. The immature lymphoid cells were mostly intermediate in size, with irregularly round nuclei, small indistinct nucleoli, and scant basophilic cytoplasm with occasional punctate vacuoles. Low numbers of mitotic figures and tingible body macrophages were also present. Cytology was consistent with lymphoid hyperplasia and plasmacytosis, with a high suspicion for concurrent lymphoid neoplasia. Serum electrophoresis revealed a monoclonal globulinopathy (M-spike) in the β region (7.3 g/dL; reference range 0.6–1.2 g/dL). Urine electrophoresis also suggested an M-spike. Immunocytochemistry of peripheral lymph nodes revealed positive immunoreactivity for CD21, CD45RA, and BLA36, and negative reactivity for CD3, CD4, CD8α, CD18, and IgG. Bone marrow cytology revealed a highly cellular specimen. Eosinophilic granular material and a moderate amount of hemosiderin were often associated with the spicules. A mild increase in the megakaryocyte number with a shift toward immaturity was noted. The M : E ratio was approximately 1 : 1. Both myeloid and erythroid cell lines were complete in maturation; however, the granulocytic line appeared mildly left shifted. Lymphoid cells were increased in number, with small, mature lymphocytes accounting for approximately 30% of all nucleated cells (ANC) and mature plasma cells mildly increased at approximately 6% of ANC. Approximately 3% of ANC involved intermediate-sized lymphocytes. This suggested a neoplastic lymphocytic proliferation. Bone marrow immunocytochemistry revealed positive immunoreactivity for CD21, CD45RA, and BLA3, and negative reactivity for CD3, CD4, CD8α, CD18, and IgG, indicating a uniform B-cell proliferation consistent with B-cell neoplasia. Serial CBCs while the dog was hospitalized revealed a persistent hyperproteinemia, and stable anemia and thrombocytopenia. Marked rouleaux formation and low numbers of intermediate-sized immature lymphoid cells were repeatable findings. The dog was discharged from the hospital with doxycycline (150 mg PO q24h), prednisoneb (20 mg PO q24h), and famotidinec (10 mg PO q24h) while awaiting qualitative immunoelectrophoresis and Ehrlichia sp. and Anaplasma phagocytophilum titers. Ehrlichia sp. and Anaplasma phagocytophilum titers were negative. Immunoelectrophoresis revealed serum monoclonal IgM gammopathy and trace urine IgM. These findings were consistent with Waldenström macroglobulinemia. Doxycycline was discontinued and melphaland was initiated at 2 mg/m2 PO q24h for 10 days, followed by a schedule of 10 days on and 10 days off for maintenance therapy. The prednisone was decreased to 40 mg PO EOD. A CBC performed 2 weeks later revealed a stable thrombocytopenia (118,000/μL). Eight weeks later, the dog was presented to the PUVTH emergency service for ataxia and possible blindness. On physical examination, the dog had horizontal nystagmus with the fast phase to the right, and hepatosplenomegaly. Ophthalmic examination revealed no new abnormalities; the retinal hemorrhages were resolving. A CBC revealed hyperproteinemia (11.5 g/dL), normocytic normochromic anemia (HCT, 23%), thrombocytopenia (142,000/μL), rouleaux formation, and rare intermediate and large immature lymphocytes. Serum biochemistry revealed mild hypercalcemia (13.0 mg/dL) and hyperproteinemia (12.4 g/dL) with hyperglobulinemia (9.7 g/dL). Prothrombin time (PT) and partial thromboplastin time (PTT) were within reference limits. Urine specific gravity was 1.020 with proteinuria (300 mg/dL) and pyuria. Abdominal was unchanged. The dog was admitted to the hospital and treated with ampicilline (20 mg/kg IV q8h) and IV lactated Ringer's solution. Ataxia and nystagmus were resolved the following day. Aspiration cytology of the spleen revealed extramedullary hematopoiesis and a heterogeneous lymphoid population. Small lymphocytes predominated, but plasmacytoid cells in various stages of maturation accounted for 15% of ANC with an increased number of intermediate and large lymphoid cells, consistent with the lymphoplasmacytic form of lymphoma; the owners declined histopathology to confirm the diagnosis and pattern of infiltration. Bone marrow cytology revealed low numbers of mostly immature megakaryocytes and a decreased M : E ratio (1 : 2) because of a greater relative erythroid response. Myeloid and erythroid cell lines appeared complete but left shifted. Low numbers of small mature lymphocytes (1% of ANC) and plasma cells (5% of ANC) were scattered throughout the specimens. A bone marrow core biopsy demonstrated a hypocellular specimen with 80% fat infiltration. Focal infiltrations of neoplastic lymphoid cells were observed along the paratrabecular areas, consisting of an intermediate-sized cell with irregularly round nuclei, moderately coarse chromatin, and small nucleoli. Mature plasma cells were observed to a lesser degree. The histologic appearance suggested metastatic involvement by a lymphoid neoplasm. The patient was discharged from the hospital the next day to continue melphalan, prednisone, and amoxicillinf (600 mg PO q12h) while awaiting urine culture results. However, the chemotherapy regimen was changed to 2 mg melphalan PO and 20 mg of prednisone PO on alternate days. An amoxicillin-sensitive Escherichia coli was cultured from the dog's urine. A CBC and serum biochemistry profile performed 4 weeks later revealed a mild anemia (HCT, 32%), thrombocytopenia (123,000/μL), elevated total protein (9.5 g/dL), and hyperglobulinemia (6.9 g/dL). Alternate-day chemotherapy was continued as prescribed previously, and the results of a CBC and serum biochemistry profile performed 8 weeks later were within reference limits. Six months later, the dog presented to the PUVTH for evaluation of an enlarged lymph node. The owner had discontinued the melphalan 3 weeks before presentation but continued giving prednisone. On physical examination, the right popliteal lymph node was found to be firm and enlarged. Aspiration cytology of the lymph node revealed a majority of intermediate-sized lymphoid cells, rare plasma cells, and low numbers of small lymphocytes, consistent with lymphoma. A CBC revealed a mild anemia (HCT, 33%) and thrombocytopenia (154,000/μL). The serum biochemistry profile was unremarkable. The urine specific gravity was 1.011 with 30 mg/dL protein. Abdominal radiographs and ultrasound were similar to previous examinations. A mild-to-moderate bronchointerstitial pattern was present on thoracic radiographs. Melphalan and prednisone were resumed every other day as recommended previously. The dog was re-examined 9 months later. Physical examination revealed no abnormalities. CBC and serum biochemistry profiles were within reference limits. Serum electrophoresis revealed a normal β fraction with a mild increase in the α fraction. Thoracic radiographs showed a very mild interstitial pattern, and abdominal radiographs showed mild splenomegaly. The owner was advised to continue alternate-day melphalan and prednisone. A CBC and serum biochemistry profile performed 1 year later revealed no abnormalities. Because the dog was clinically normal >3.5 years after initial diagnosis, the owner became resistant to aggressive monitoring, but continues giving alternate-day melphalan and prednisone. Waldenström's (IgM) macroglobulinemia is a rare lymphoproliferative disorder in dogs, cats, and humans.1, 2 This clinical presentation is characterized by clonal expansion of small B lymphocytes producing an IgM serum paraprotein. It is considered, by the WHO classification, as a form of lymphoplasmacytic lymphoma involving the spleen, lymph nodes, and bone marrow, along with serum IgM-related signs of hyperviscosity or cryoglobulinemia.3 Bence-Jones proteinuria is an uncommon finding in Waldenström's macroglobulinemia.1-7 Bony lysis seen with plasma cell neoplasms such as myeloma is not present with lymphoplasmacytic lymphoma. The production of IgM paraprotein may be associated with other forms of B-cell lymphoma, including splenic marginal zone lymphoma, B-cell lymphocytic leukemia, or rarely extranodal marginal zone lymphoma.3 In this dog, the morphologic features of a mixed lymphoid cell population with low numbers of plasma cells support a diagnosis of lymphoplasmacytic lymphoma, with Waldenström macroglobulinemia. In this dog, serum protein concentrations were consistently higher than plasma concentrations. Although instrumentation methods may be partly responsible, serum protein concentration is generally lower because of loss of fibrinogen. The cause for disparity in this dog is unknown, but may be due to cryoproteins.8 A decrease in plasma protein occurs with cooling during centrifugation of the microhematocrit tube and cryoproteins settling before refractometer reading. When the smooth uncut end of the microhematocrit tube is used to fill the refractometer, it contains fewer dense immunoglobulins because higher molecular weight IgM molecules settle closer to the cut end at the cell–fluid interface. Pathologic conditions associated with Waldenström's (IgM) macroglobulinemia include bleeding tendencies, hyperviscosity syndrome (HVS), renal disease, cardiovascular disease, hypercalcemia, and cytopenias.1, 2 Bleeding diathesis occurs in approximately 33% of dogs.9 Although the cause is unknown in dogs, it may result from M components interfering with platelet aggregation or clotting factors.9-11 HVS occurs with IgM macroglobulinemia because the large IgM molecules lead to higher serum viscosity than with comparable serum concentrations of IgG and IgA. In humans, clinical signs of HVS include fatigue, blurred vision, headache, shortness of breath, mucosal bleeding, dementia, and coma.1 Lethargy, bleeding tendencies, cardiac insufficiency, retinopathies, and renal damage are reported in canine IgM macroglobulinemia.2, 4-7, 9, 11-15 Nervous system involvement is also reported, resulting in altered mental status, ataxia, or coma.2, 11, 13, 14 Intention tremors are described in dogs with IgM macroglobulinema.11, 13 This dog developed vestibular signs, which resolved with fluid therapy, suggesting that they were a result of HVS. Treatment is directed at reducing tumor burden and alleviating clinical signs, because many dogs will not have complete remission.9 Prognostic factors for treatment response and survival are unknown. Treatment for canine IgM macroglobulinemia consists of alkylating agents and prednisone, and approximately 77% of dogs with IgM macroglobulinemia respond with a median survival time of 11–14 months.9, 11 Chlorambucil and prednisone are described most frequently.1, 2, 4, 6, 9, 11, 12, 14 Used infrequently, melphalan and cyclophosphamide have clinical activity in dogs with IgM macroglobulinemia;9, 11, 15 the melphalan schedule in previous reports is unclear.11, 15 After 8 weeks of 10 days on and 10 days off melphalan, there was no response in this dog. Alternate-day melphalan resulted in normalization of laboratory tests within 12 weeks, suggesting that dose schedule may improve treatment response. In humans, metronomic chemotherapy causes clinical response when dose-intense chemotherapy has failed.16-18 This dog is unique because alternate-day melphalan and prednisone provided a durable remission. aDoxycycline Hyclate tablets, West-Ward Pharmaceuticals Corporation, Eatontown, NJ bPrednisone tablets, Roxane Laboratories, Inc., Columbus, OH cFamotidine dAlkeran, GlaxoSmithKline, Research Triangle Park, NC eAmpicillin injection, American Pharmaceutical Partners Inc, Schaumburg, IL fAmoxi-Tabs, GlaxoSmithKline The authors acknowledge Michele Plier, DVM, DACVP, for clinical pathology contributions as well as Amalia deGortari, MVZ, and Rosanne Thomas, RVT, for their technical assistance with this case.

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