Treatment of relapsed or refractory Waldenström's macroglobulinemia with bortezomib.

BACKGROUND AND OBJECTIVES: Bortezomib is a selective proteasome inhibitor which has shown significant activity in a variety of hematologic malignancies including multiple myeloma, mantle cell lymphoma and marginal zone lymphoma. Thus, this agent is worth studying in patients with Waldenström's macroglobulinemia (WM). DESIGN AND METHODS: Patients with refractory or relapsed WM were treated with bortezomib administered intravenously at a dose of 1.3 mg/m2 on days 1, 4, 8 and 11 in a 21-day cycle for a total of four cycles. RESULTS: Ten previously treated patients with WM were treated with bortezomib. Most patients had been exposed to all active agents for WM and eight patients had received three or more regimens. Six of these patients achieved a partial response which occurred at a median of 1 month. The median time to progression in the responding patients is expected to exceed 11 months. Bortezomib was relatively well tolerated. The more common toxicities were mild or moderate thrombocytopenia, fever and fatigue while peripheral neuropathy occurred in three patients and one patient developed severe paralytic ileus. INTERPRETATION AND CONCLUSIONS: Our preliminary data indicate that bortezomib is an active agent in patients with heavily pretreated relapsed/refractory WM. Four cycles of this agent may be adequate to assess sensitivity in this disease. Further studies are needed to confirm our results and to evaluate combinations of bortezomib with other active agents.

Differential diagnosis of Waldenstrom's macroglobulinemia and other B-cell disorders.

Waldenstrom's macroglobulinemia (WM) is characterized by lymphoplasmacytic infiltration of bone marrow and/or other tissues and by the presence of serum monoclonal immunoglobulin M ([IgM], without cutoff limit). Differential diagnosis from other B-cell disorders (BCDs) is usually easy based on clinical, morphologic, histopathologic, immunophenotypic, and genetic features. However, all BCDs potentially produce monoclonal IgM. In this study we reviewed the medical files of 130 patients with IgM-secreting BCDs. Eighty-four patients were diagnosed with WM, 5 with IgM-monoclonal gammopathy of undetermined significance (MGUS), and 41 with other BCDs (9 with B-cell chronic lymphocytic leukemia, 5 with small lymphocytic lymphoma, 14 with marginal zone lymphoma, 5 with mantle-cell lymphoma, 2 with follicular lymphoma, 2 with diffuse large B-cell lymphoma, 2 with cryoglobulinemia, and 2 with low-grade lymphoma not otherwise specified). Median IgM levels were 3215 mg/dL in WM, 840 mg/dL in IgM-MGUS, and 285 mg/dL in other BCDs (5 had IgM levels > 1500 mg/dL). In 10% of non-WM BCDs, monoclonal IgM was found only when more sensitive immunofixation methods were used. Forty-four percent of patients with BCDs (splenic marginal zone lymphoma or small lymphocytic lymphoma) had diagnoses that corresponded to that of WM. Careful diagnosis requires the concomitant evaluation of all parameters of BCDs together. Marginal zone lymphoma is the most frequently overlapping entity. Special attention should be given to mantle cell lymphoma in its atypical forms. Research in this field should continue to further clarify the disease entities that overlap with WM. New technology such as gene-expression profile techniques may contribute to this purpose.

Transient left ventricular dysfunction in Churg Strauss syndrome: a case report.

A 42 year old woman was admitted to our hospital for investigation of eosinophilia. There were no findings from the physical examination of the lungs and heart. The echocardiography showed a segmental hypokinesia of the interventricular septum and the apex causing left ventricular dysfunction with an ejection fraction 45% and mild pericardial effusion. Cardiac magnetic resonance was performed, for detection of lesions associated with the underline disease, using electrocardiogram-triggered T2-weighted and T1-weighted multislice spin-echo images (before and after an intravenous bolus of gadolinium).The analysis of T2-weighted images revealed increased signal on the mid part of interventricular septum, suggesting myocardial oedema. In the delayed-enhanced images, areas of late phase gadolinium enhancement (indicative of fibrosis) were identified in the mid part of interventricular septum. Methylprednisolone therapy was started. The patient had follow-up echocardiographic examination every month and on sixth month improvement of left ventricular dysfunction was shown with an ejection fraction 55%.In conclusion our case is a typical Churg Strauss Syndrome with characteristic myocardial involvement which improved after corticosteroid treatment. The cardiac magnetic resonance has significant role for early and accurate detection and differentiation of myocardial damage even in preserved cardiac wall motion and cavity size.

T cell lymphoblastic lymphoma in parotidectomy for Warthin's tumor: case report and review of the literature.

Lymphomas associated with Warthin's tumor (WT) are extremely uncommon and the majorities are of B cell type. We report the simultaneous occurrence of T-cell lymphoblastic lymphoma (T-LBL) and WT in an 81-year-old patient, who presented with fever, night sweats and enlargement of the right parotid gland. The parotidectomy specimen showed a WT with extensive replacement of the lymphoid stroma by T-LBL, but preservation of the oncocytic epithelium. Staging investigations revealed mediastinal and abdominal lymphadenopathy, bilateral pleural effusions and bone marrow infiltration, in keeping with stage IVB disease. The patient received combination chemotherapy treatment but responded poorly, and died three months after diagnosis. To our knowledge, this is the first case report of T-LBL involving WT. The present study indicates that the lymphoid stroma in WT belongs to the systemic lymphoid tissue and can be involved in disseminated lymphoma. It highlights the importance of careful examination of WT's lymphoid stroma for the possible presence of any coexistent malignancy.

Non-gastric extra-nodal marginal zone lymphomas--a single centre experience on 76 patients.

In the present study, we assessed the clinical and pathological data of 76 patients with the diagnosis of non-gastric extranodal marginal zone B-cell lymphoma. The most commonly affected sites were salivary glands, skin, ocular adnexa, lung, intestine and Waldeyer's ring. Ann Arbor stage I disease was present in 39 patients (51%), stage II in 10 (13%) and stage IV in 27 (36%). In 17 cases (21%), the lymphoma presented at multiple mucosal sites. Lymph node and bone marrow involvement were present in 21% and 16%, respectively. Most cases were in the low or low-intermediate risk group. Treatment was heterogeneous and included chlorambucil in 59% either alone or in combination with other agents. Complete and partial remission was achieved in 79% and 7%, respectively, with an overall response rate of 86%. The 5- and 10-year overall survival and cause-specific survival rates were 94%, 82% and 95%, 91%, respectively. The 5- and 10-year progression free survival was 56% and 41%, respectively. The only feature associated with inferior outcome was disease localisation to the lung.

Favorable outcome of primary cutaneous marginal zone lymphoma treated with intralesional rituximab.

Primary cutaneous marginal zone lymphoma (PCMZL) is an indolent disease. Treatment options include excision, local irradiation, interferon-alpha or chemotherapy. We present two patients with PCMZL and multiple skin lesions successfully treated with intralesional administration of the anti-CD20 monoclonal antibody rituximab. The first presented with four red skin lesions and the second with two. Biopsy of the largest lesion revealed marginal zone B-cell lymphoma in both patients. There was no evidence of systemic involvement in either patient. Both patients were treated with intralesional rituximab for 18 consecutive weeks. Skin lesions gradually regressed. Apart from mild local pain during the injection, no other adverse effects were observed. In conclusion, rituximab can be safely administered intralesionally in patients with PCMZL and can produce disease remission.

Expression patterns of Th1 and Th2 cytokine genes in childhood idiopathic thrombocytopenic purpura (ITP) at presentation and their modulation by intravenous immunoglobulin G (IVIg) treatment: their role in prognosis.

Childhood idiopathic thrombocytopenic purpura (ITP) resolves usually after the first episode, although it may recur, and in 10% to 20% of patients develops into a chronic disorder. Evidence of the immunoregulatory role of Th1/Th2 responses in autoimmune diseases prompted us to perform a prospective study of Th1/Th2 gene expression profiles and transforming growth factor beta (TGF-beta) plasma levels in 18 children (median age, 6.4 years) with acute ITP, before and after intravenous immunoglobulin G (IVIg) infusion, and during a follow-up period (0.5-5 years). Initially, 12 of 18 patients had either low Th0/Th1 plus interleukin 10 (IL-10) or no in vivo cytokine gene expression (0). At 24 hours after IVIg infusion this pattern became 0 or Th2 (9 of 12) or remained low Th0/Th1 (3 of 12). During follow-up these patients did not relapse and maintained 0 or Th2 pattern without IL-10. Of the remaining 6 patients, 4 presented with a Th1 or Th0/Th1 pattern plus IL-10 that persisted after IVIg treatment (although interferon gamma [IFN-gamma] expression diminished) and stabilized to Th1 plus IL-10 at follow-up, which was marked by infrequent episodes of ITP. Two patients presenting with a strict Th1 pattern characterized by high expression of IFN-gamma, which remained unchanged after IVIg and at follow-up, can be characterized as chronic ITP. TGF-beta plasma levels were low in patients with active disease and increased in remission. Overall, acute ITP presents with Th1, Th0/Th1, or 0 in vivo cytokine gene expression. Stable remission is associated with a 0 or Th2 pattern. A 0 or Th2 pattern after IVIg gave the best prognosis, whereas sustained high expression of IFN-gamma and refractoriness to IVIg were the main indicators of poor prognosis.

Serum syndecan-1, basic fibroblast growth factor and osteoprotegerin in myeloma patients at diagnosis and during the course of the disease.

UNLABELLED: Neovascularisation and bone resorption are related to myeloma disease activity. OBJECTIVES: To investigate the possible prognostic importance of serum syndecan-1, basic fibroblast growth factor (bFGF) and osteoprotegerin (OPG) levels, the relationship between them, with parameters of disease activity and the effect of treatment on their levels. PATIENTS AND METHODS: Twenty-seven patients were studied from diagnosis and an additional five from remission, for a median follow-up of 40 months. Twenty-three patients received chemotherapy plus bisphosphonates and nine only bisphosphonates. Sera from 11 healthy individuals (HI) were used as controls. Cytokines were determined by commercially available enzyme-linked immunosorbent assays (ELISA) kits. RESULTS: In HI, median syndecan-1 was 40 ng/mL (28-75), bFGF 8 pg/mL (7-30), OPG 35 pg/mL (4-100). Pretreatment median serum syndecan-1 was 177.5 ng/mL (34-3500), bFGF 11.5 pg/mL (8-65) and OPG 100 pg/mL (4-1000). Pretreatment syndecan-1, bFGF and OPG serum levels were increased in patients compared with HI (P = 0.001, 0.03 and 0.01, respectively). Syndecan-1 and bFGF levels were correlated with stage (P = 0.004 and 0.03, respectively). Both syndecan-1 and OPG levels were correlated with beta2M (P = 0.04 and 0.01, respectively). Patients with elevated syndecan-1 and bFGF serum levels had shorter survival than patients with normal levels (P = 0.01 and 0.05, respectively). After chemotherapy syndecan-1 and OPG levels were found to be decreased in responders and syndecan-1 level was reduced in patients receiving bisphosphonates alone. CONCLUSIONS: Pretreatment syndecan-1, bFGF and OPG levels were found to be increased at diagnosis. Syndecan-1 and OPG fluctuated according to MM activity. Elevated serum syndecan-1 and bFGF levels predicted short survival.