Resolution of Waldenström's macroglubulinemia related isolated neutropenia by immunochemotherapy
Authors: Michel van Gelder, Ariënne van Marion, Valère Goossens, Martin Bommer, Véronique Leblond
Journal: American Journal of Hematology (2011)

Waldenström's macroglobulinemia (WM) can give rise to several clinical symptoms. The most well known are hyperviscosity due to highly increased levels of monoclonal IgM and anemia due to bone marrow involvement. In some patients, WM induces chronic inflammation characterized by increased CRP [1]. We now report a unique clinical presentation in a WM patient with chronic inflammation from onset on, who after several years developed agranulocytosis during a watch and wait policy. The bone marrow biopsy then showed, besides infiltration by plasmacytoid lymphocytes, maturation arrest in the granulopoiesis. Toxic and infectious causes were excluded. Immunochemotherapy, consisting of the alkylating agent chlorambucil and rituximab, was started after given informed consent. This treatment resulted in a very good partial remission of WM, resolution of the inflammatory state, and also in full recovery of neutrophil counts, pointing to the relation of the agranulocytosis with the WM. In May 2006, WM was diagnosed in a 54-year-old male with no medical history. The disease had come to light because of slight anemia found in a routine blood analysis. There were no obvious complaints. The hemoglobin level was 6.9 mmol/l (normal range 8.2–11.0 mmol/l), MCV 87, and reticulocytes 0.8%. Leukocyte count was normal (5.7 × 109/l) as was the differentiation (58% neutrophils, 19% lymphocytes, 16% monocytes, 5% eosinophils, 2% basophils) although some lymphocytes were plasmacytoid. Thrombocytes were elevated (582 × 109/l). The total protein level was 86,8 gr/l and the protein-electrophoresis showed a distinct band in the beta fraction, representing monoclonal IgM kappa by immune fixation. The total IgM level was 26 g/l. The CRP level was 46 mg/l and the albumin 33 g/l. Microscopic examination of multiple bone marrow smears showed infiltration by 20–63% plasmacytoid lymphocytes and an excess of mast cells. There was normal maturation of residual erythropoieis, megakarypoiesis, and granulopoiesis. The iron staining showed ample iron storage but no iron incorporation, compatible with anemia of chronic disease (ACD). Immunophenotyping of the bone marrow aspirate proved the lymphocytes to be monoclonal B-cells, CD19, CD20, CD79a, FCM7, and surface IgM kappa positive and CD5 and CD10 negative. The bone marrow biopsy showed foci of plasmacytoid lymphocytes, CD20 positive, cycline D1 and CD23 negative, IgM kappa positive, negative for IgG, IgA, IgD, and lambda. As the patient did not have symptomatic hyperviscosity or complaints of the slight anemia, a “watch and wait” strategy was started. The inflammatory state characterized by the elevated CRP level, ACD, thrombocytosis and hypoalbuminemia persisted throughout the years (Table I). His disease state did not change until December 2008, when he was admitted to another hospital because of high fever. There were no other symptoms, and the cause of fever was never found; blood cultures remained negative. The laboratory tests however showed absolute neutropenia (0.0 × 109/l), a slight decrease in the hemoglobin level and a lower thrombocytes count than usual, now being within the normal range. CRP was more elevated than before (100 mg/l). After treatment with broad-spectrum antibiotics the fever disappeared, and the CRP level decreased to its original increased level as did the number of red blood cells and thrombocytes. The amount of monoclonal IgM had not changed during this febrile episode and remained stable over the following time. The neutrophils however remained undetectable for at least more than a year, inducing recurrent herpes simplex virus induced mucositis of the oral cavity. An extensive analysis was then started. Repeatedly taken bone marrow aspirates, taken 6 months apart, only showed numerous lymphocytes. The bone marrow biopsies revealed in addition to abundant B-lymphocytes normal erytropoiesis and thrombopoiesis. Neutrophil precursors were easily found but for mature neutrophils, indicating neutrophilic maturation arrest (Fig. 1). No granulomas were observed. The differential diagnosis included drug-induced toxicity, various infectious diseases, T/NK large granular lymphocytic (LGL) leukemia, autoantibody mediated and, by exclusion, M. Waldenström-related. The only medication patient took for years comforting back pain was Ibuprofen, occasionally causing granulocytic maturation arrest [2]. Five months after cessation of this drug neutropenia persisted. No other medication had been prescribed. Travel history did not reveal any visits to Asia, Africa, or South America. Serological tests revealed past infection by CMV, EBV, and parvovirus B19 as evidenced by the presence of specific IgG antibodies. CMV- and EBV-PCR were negative in the blood. PCR for parvovirus B19 was negative in the blood but slightly positive in the cell fraction of the bone marrow aspirate. The bone marrow biopsies were negative in the Ziehl-Neelsen staining and did not reveal any granulomas. Bone marrow cultures remained negative for Mycobacteria as was the PCR for M. tuberculosis and for atypical species. Examination of blood smears did not reveal an increase of LGLs, and no abnormal subpopulations of T or NK cells characterized by marker loss were found by immunophenotyping. No clonal T cell population was detected by molecular T cell receptor gene rearrangement studies. Direct testing for the presence of neutrophilic auto-antibodies was impossible due to the absolute neutropenia. The patient's serum however did not contain antineutrophil antibodies. Although parvovirus B19 infection was not suspected due to the absence of characteristic erytroid precursor abnormalities and the rather low level of viral replication as measured by PCR, chronic parvovirus B19 infection was considered a possible cause of the neutropenia [3-6]. Because some case reports suggest a beneficial effect of high-dose polyclonal immunoglobulin infusion on chronic parvovirus B19 infection [4, 6], IVIG was infused two times four months apart in a dose of 2 g/kg, respectively. Three months after the last IVIG administration neutrophils remained undetectable. The patient was then proposed to start therapy for WM. When he finally overcame his reluctance to chemotherapy, immunochemotherapy was started 6 months after the last IVIG administration. As the patient preferred the lowest possible toxicity profile including no hair loss, it was decided to prescribe the alkylating agent chlorambucil (0.1 mg/kg/day p.o.) combined with rituximab (375 mg/m2 i.v. 4 weeks apart) closely resembling the highly effective dexamethasone, rituximab and cyclophosphamide scheme [7]. From 3 weeks after starting immunochemotherapy, total protein level decreased and albumin level increased, reflecting inhibition of monoclonal IgM production (Table I). At the same time, the CRP level and the thrombocyte count decreased to normal levels, and the haemoglobin level increased to normal levels. More importantly, neutrophils became detectable and gradually rose to normal levels within 4 months after onset of immunochemotherapy and remained at this level at the last moment of follow-up at 4 months after cessation of therapy (Table I). Because of the time relation between start of therapy, the normalization of neutrophils count and improvement of all of his WM features, we conclude that this patient must have suffered from WM-related specific granulocytic maturation arrest. Bone marrow biopsy taken in February 2010, i.e., early after onset of agrunolocytosis. A: hypercellular bone marrow (HE staining, 50× magnification); B: abundance of plasmacytoid lymphocytes among normal erytroid and granulocytic precursors (HE staining, 400× magnification); C: Myeloperoxidase (MPO) staining shows the presence of neutrophilic precursors but absence of nuclear segmented neutrophils (immunohistochemistry staining with mouse anti-human MPO primary antibody and biotine labeld anti-mouse Ig conjugated secondary antibody, followed by protein block and avidine horse radish peroxidase, counterstained with hematoxylin, 630× magnification). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Michel van Gelder*, Ariënne van Marion , Valère Goossens , Martin Bommer§, Véronique Leblond¶, * Department of Internal Medicine, Hematology division, Maastricht University Medical Center, Maastricht, The Netherlands, Department of Pathology, Maastricht University Medical Center Maastricht, The Netherlands, Department of Microbiology, Virology division, Maastricht University Medical Center, Maastricht, The Netherlands, § Klinik für Innere Medizin III, Hämatologie, Onkologie, Rheumatologie und Infektionskrankheiten Universitätsklinikum Ulm, Germany, ¶ Hospital Pitié Salpêtrière APHP, Université Pierre et Marie Curie, Paris, France.