A case of multicentric Castleman's disease associated with advanced systemic amyloidosis treated with chemotherapy and anti-CD20 monoclonal antibody

Multicentric Castleman's disease (MCD) is a rare systemic lymphoproliferative disorder with too few patient series reported in the literature to have a clear idea about the etiology, outcome and the best treatment available. Systemic reactive amyloidosis is a very rare complication of MCD and its presence worsens the prognosis. We report a case of a 28-year-old patient with plasma-cell type, human immunodeficiency virus (HIV)-negative and human herpesvirus-8 (HHV-8)-negative MCD who responded to treatment with chemotherapy and the anti-CD20 monoclonal antibody, rituximab. Anti-CD20 therapy could be an interesting adjunctive treatment in MCD.     

The presence of CD28-negative T cells in a patient with multicentric Castleman's disease

 We found increased numbers of CD28-negative T cells in a patient with multicentric Castleman's disease (MCD), who also had significantly decreased interleukin-2 (IL-2) production and impaired T-cell proliferation. The presence of CD28-negative T cells may be indicative of a functional T-cell defect in MCD. Received: 19 March 1996 / Accepted: 15 May 1996     

Pure red cell aplasia: Clinical features and treatment results in 16 cases

 Pure red cell aplasia (PRCA) is a rare hematological disease characterized by selective marrow erythroid aplasia. We report the clinical features and treatment results of 16 Chinese patients with PRCA. Nine (56%) cases were not associated with any underlying disorders and were considered idiopathic, while seven patients (44%) had associated diseases, three involving the thymus, two with T large granular lymphocyte leukemia (T-LGLL), and one each with Stevens-Johnson syndrome and acute hepatitis A. Conventional-dose corticosteroid therapy resulted in complete remission in three of 13 patients. Cyclosporin A was used in six patients. There were three complete and one partial remissions. High-dose methylprednisolone was ineffective in four patients who failed conventional-dose corticosteroids but achieved complete remission in one patient with thymoma who did not respond to thymectomy. Antithymocyte globulin was used in four patients, resulting in partial remission in only one patient with concomitant T-LGLL. Intravenous gamma globulin and danazol were ineffective in three patients. Thymectomy was performed in two patients, with one patient remitting. This is the largest series of PRCA reported in an oriental population. Our results indicate that treatment of PRCA may still be problematic and better therapeutic strategy will have to be defined. Received: 11 September 1995 / Accepted: 1 January 1996     

Interleukin-6 receptor expression in the peripheral B cells of patients with multicentric Castleman's disease

 Interleukin-6 (IL-6) is an important regulator of terminal B-cell differentiation. Inappropriate oversynthesis of IL-6 may play a primary role in the pathogenesis of multicentric Castleman's disease (MCD). We investigated the expression of the IL-6 receptor (IL-6R) in peripheral B cells from three patients with MCD, as well as the responsiveness of these cells to IL-6. Flow-cytometric analysis showed that IL-6R was significantly expressed on the peripheral B cells of two of three patients. The B cells expressing IL-6R spontaneously produced increased levels of immunoglobulin G (IgG). IL-6R-expressing B cells from one patient showed hyper-responsiveness to IL-6. Received: 6 March 1996 / Accepted: 12 June 1996     

The clinical characteristics and therapy response of patients with acquired pure red cell aplasia

ABSTRACT

Objective: To summarize the clinical characteristics of acquired pure red cell aplasia (PRCA) patients diagnosed in our hospital in the last 10 years.

Method: The clinical features, immune state and treatment response of acquired PRCA patients diagnosed in our hospital from January 2007 to January 2017 were retrospectively analyzed.

Results: The results showed that thymoma (13.21%) and parvovirus B19 (11.32%) were the most common causes for secondary PRCA. Ferritin (Fer) levels and erythropoietin (EPO) levels were increased in PRCA patients. The total CR and PR rate of immunosuppressive therapy in our studies was 68.29% and 12.20%, respectively. Patients with EPO level >400 U/L and Fer level >200?ng/ml had significantly lower CR rate than others. The patients with EPO level >400 U/L also had longer hemoglobin recovery time than patients with EPO level ≤400 U/L. Patients treated with corticosteroids (CS)?+?cyclosporine A (CsA) had lower relapse rate compared to the CS group (29.17% vs. 80.00%, P?<?.05).

Conclusion: Our data showed that patients with PRCA had high EPO and Fer levels. Thymoma and viral infections are the most common causes for secondary PRCA. The CS+ CsA group had lower relapse rate than CS group although response rate was similar. Increased EPO and Fer levels might be the negative factors for prognosis of acquired PRCA.     

Hodgkin's and Castleman's disease in a patient with systemic mastocytosis

 Systemic mastocytosis is a rare condition characterized clinically by the local consequences of vasoactive peptides released from infiltrating mast cells in the reticuloendothelial tissues. Mast cells originate from the pluripotent bone marrow stem cells; it is therefore not surprising that myeloproliferative and myelodysplastic disorders commonly coexist or terminate the clinical phase of mastocytosis. We report here, to our knowledge, the first case of Hodgkin's and Castleman's disease occurring in a patient with co-existent systemic mastocytosis, which remained unchanged after combination chemotherapy for Hodgkin's disease. Received: December 18, 1997 / Accepted: September 8, 1998     

Serum erythropoietic inhibitors in patients with pure red cell aplasia

Summary Inhibitory mechanisms of erythropoiesis in 20 patients with pure red cell aplasia (PRCA) were investigated using the technique of in vitro hematopoiesis and an assay for human parvovirus. Complement-dependent serum inhibitors against late erythroid progenitors (CFU-E) were demonstrated in seven of 19 patients examined, and complement-dependent inhibitors against early erythroid progenitors (BFU-E) were demonstrated in three of these seven patients. Nonspecific and complement-independent inhibitors against CFU-E were thought to be associated with the etiology of PRCA in one patient. Human parvovirus-mediated erythropoietic suppression was demonstrated in a patient with complete remission of acute lymphoblastic leukemia complicated with marrow erythroid aplasia, whose serum showed a perfect inhibition against erythroid progenitor cells. T-cell-mediated erythroid suppression was not demonstrated in the patients examined. These findings reveal that erythroid aplasia is associated with complement-dependent serum erythropoietic inhibitor in some patients (36.8% in the present study) with PRCA, but it is difficult to identify the mechanism of erythroid aplasia in more than half of the patients with PRCA. In addition, our present study discovered the presence of parvovirus-mediated marrow pure red cell aplasia in one adult patient with acute lymphoblastic leukemia.     

Acquired pure red cell aplasia in Japan

Abstract: We reviewed the clinical features of 150 patients with acquired pure red cell aplasia (PRCA) in Japan. There were 35 patients with acute type and 115 with chronic type PRCA. Of the acute PRCA patients, 17 had human parvovirus B19 infection. Drug-induced PRCA was demonstrated in 7 patients. Of the 115 patients with chronic PRCA, 51 patients were classified as primary and 64 cases were associated with miscellaneous diseases such as thymoma, a variety of hematological disorders and collagen diseases. Among the hematological disorders, PRCA was most frequently seen in granular lymphocyte proliferative disorders (GLPD). The erythroid colony growth patterns from bone marrow were variable. The serum erythropoietin level was high in most patients. Various kinds of treatment were tried for the chronic PRCA cases. Cyclosporin A (CyA) was the most effective form of treatment and the response rate was 82% (31/38). Twenty-three of 37 patients (62%) responded to bolus methylprednisolone therapy. The largest number of patients were treated with oral prednisolone, and the therapy was effective in 27 of the 55 (49%). The response rate to cyclophosphamide was only 29% (5/17), but in combination with prednisolone, half of the patients (7/14) responded to the therapy. CyA is recommended as the first-line therapy for acquired chronic PRCA.     

Splenectomy induced complete remission in a patient with multicentric Castleman's disease and autoimmune hemolytic anemia

 Castleman's disease (CD) is a rare disorder of the lymphoid tissue in which the clinical manifestations often mimic a malignant lymphoma. Despite the absence of monoclonality of the lymphoid proliferation, the multicentric variant of the disease (MCD) is characterized by severe symptoms and poor prognosis. Etiologic, pathogenetic, and therapeutic aspects of MCD are still uncertain. We report the case of a 57-year-old patient affected by MCD complicated by severe immunohemolytic anemia. Whereas the clinical and laboratory response to steroids and chemotherapeutic agents was only partial, splenectomy induced a complete remission of hemolysis and disappearance of the constitutional symptoms and of all generalized lymphadenopathies. Received: April 6, 1998 / Accepted: November 26, 1998     

Spontaneous IL-2 production in vitro in two patients with pure red cell aplasia

Summary We investigated spontaneous cytokine production in two patients with pure red cell aplasia (PRCA). The peripheral blood mononuclear cells (PBMNC) from two patients produced IL-2. Cyclosporin A (CyA) suppressed in vitro IL-2 production in one patient, but not in the other. Spontaneous IL-2 production disappeared in one patient 10 months after the start of CyA therapy. The patient for whom CyA therapy was stopped after the disappearance of spontaneous IL-2 production has remained in continuous remission for 1 year. The present case suggests that spontaneous IL-2 production in PBMNC might be an indicator of disease activity.     

Hodgkin disease and red cell aplasia

A teenage boy with mixed-cellularity Hodgkin disease presented with severe anemia secondary to pure red cell aplasia of marrow without evidence of lymphomatous infiltration or hemolysis. In vitro studies of the patient's serum demonstrated an inhibitor of erythropoietin activity which appeared to be an IgG but which did not directly bind erythropoietin. The patient's anemia resolved and the inhibitor disappeared following chemotherapy for Hodgkin disease. Presumably, the inhibitor was directed at a very early stage of red blood cell production. This phenomenon may be related to other autoimmune manifestations occasionally seen in patients with lymphomas. The case is presented to bring attention to the unusual occurrence of red cell aplasia in Hodgkin disease. Several hypotheses concerning significance and etiology of the anemia are detailed.     

Sirolimus for the treatment of multi-resistant pure red cell aplasia

Patients with relapsed, refractory or advanced stage B non-Hodgkin lymphoma (NHL) continue to have a dismal prognosis. This review summarises current and novel cellular and immunotherapy for these high-risk populations, including haematopoietic stem cell transplant, bispecific antibodies, viral-derived cytotoxic T cells, chimeric antigen receptor (CAR) T cells, and natural killer (NK) cell therapy, as discussed at the 6th International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin Lymphoma on September 26th–29th 2018 in Rotterdam, the Netherlands, and explores the future of NK/CAR NK therapies.     

Cyclophosphamide therapy for pure red cell aplasia associated with granular lymphocyte-proliferative disorders

Granular lymphocytes have been characterized as cells with azurophilic granules in the cytoplasm. Patients with increased numbers of granular lymphocytes are designated as granular lymphocyte-proliferative disorders (GLPDs). A variety of haematological abnormalities are associated with T-cell-lineage GLPD. Among these, pure red cell aplasia is frequent, and adequate therapy is required. Seven patients with pure red cell aplasia, or a related condition complicating T-cell-lineage GLPD, were entered into this study. Cyclophosphamide was initiated at a daily oral dose of 100 mg. After 2 weeks the dose was reduced to 50 mg/d, and maintained at that dose. Cyclophosphamide was administered until the lymphocyte count was <1 ×10⁹ l and T-cell receptor-β gene analysis was used to monitor the response to treatment. All the patients were successfully treated, irrespective of their former treatment. Clinical remission was associated with the disappearance of the abnormal granular lymphocyte clone, as detected by Southern blot hybridization analysis. Therapeutic responses began after 8 weeks, and clinical complete remissions were obtained after 6 months. Oral cyclophosphamide monotherapy can successfully treat the pure red cell aplasia associated with T-cell-lineage GLPD.     

Monoclonal gammopathy‐associated pure red cell aplasia

Pure red cell aplasia (PRCA) is a rare disorder characterized by inhibition of erythroid precursors in the bone marrow and normochromic, normocytic anaemia with reticulocytopenia. Among 51 PRCA patients, we identified 12 (24%) patients having monoclonal gammopathy, monoclonal gammopathy of undetermined significance or smouldering multiple myeloma, with presence of monoclonal protein or abnormal serum free light chains and atypical bone marrow features of clonal plasmacytosis, hypercellularity and fibrosis. Thus far, three patients treated with anti‐myeloma based therapeutics have responded with reticulocyte recovery and clinical transfusion independence, suggesting plasma cells play a key role in the pathogenesis of this specific monoclonal gammopathy‐associated PRCA.     

A case of pure red cell aplasia complicated by Evans syndrome

A 33-year-old woman complaining of severe anemia was admitted to our hospital for polyclonal hyperglobulinemia. She was diagnosed with pure red cell aplasia (PRCA) associated with Evans syndrome. Initially, the presence of human parvovirus B19 (HPV B19) IgM appeared to indicate that the cause of PRCA was HPV B19 infection. Evans syndrome improved with steroid therapy, but PRCA was refractory. Cyclosporine was administered; consequently, the patient markedly recovered from PRCA and was discharged. PRCA complicated by Evans syndrome occurred during the course of polyclonal hyperglobulinemia. The most direct etiology for the onset of PRCA was unclear; however, immunological disorders such as polyclonal hyperglobulinemia, in addition to HPV B19 infection, may have been partly responsible for the etiology of PRCA.     

Successful treatment of pure red cell aplasia with high-dose dexamethasone after ABO-incompatible allogeneic hematopoietic stem cell transplantation

The literature reports an incidence of Pure Red Cell Aplasia (PRCA) ranging from 6-30% of all cases of ABO-incompatible HSCT. Although most patients resolve spontaneously after withdrawal immunosuppression, some of them require more aggressive treatment to manage this condition.     

Severe acute hepatitis A associated with acute pure red cell aplasia

A rare case of severe acute hepatitis A complicated by pure red cell aplasia (PRCA) is reported. A 60-year-old man with jaundice and hepatomegaly was diagnosed as having acute hepatitis A by positive IgM anti-hepatitis A antibody (anti-HAV). Severe anemia rapidly developed 3 weeks after admission, and the patient was diagnosed with PRCA by both bone marrow smears and crythrocyte survival study. The anemia was transient and bone marrow recovered within 1 week. However, concomitant with bone marrow recovery, the hepatitis worsened. He became drowsy and disoriented and severe jaundice, ascites, prolonged prothrombin time, increased transaminase levels, and abnormal electroencephalogram (EEG) were exhibited. Plasma exchange transfusion and glucagon-insulin (GI) therapy improved the consciousness level, but bilirubin, transaminase levels, and IgM anti-HAV titer remained high. Intravenous administration of lipophilized prostaglandin E₁ (lipo-PGE₁) was added to the GI therapy. Bilirubin and transaminase levels were normalized in the 8th week after the initiation of this combination therapy (17 weeks after admission). The combined use of lipo-PGE₁ with plasma exchange and GI therapy appeared to be useful for the prolonged severe hepatitis in this patient.     

Chronic myeloid leukemia associated with pure red cell aplasia and terminating in promyelocytic transformation

After intermittent treatment with busulphan over a 7-year period for chronic myeloid leukemia (CML) in chronic phase, a 39-year-old female developed leukocytosis in association with pure red cell aplasia (PRCA). Bone marrow examination confirmed erythroid aplasia, and culture revealed a total absence of erythroid progenitor cells. The patient then was treated with azathioprine, corticosteroids, cyclophosphamide, plasma exchange, and cyclosporin A, but she remained erythroblastopenic and transfusion dependent for more than a year, at which time a promyelocytic transformation supervened. The authors propose that this sequence of events, hitherto unreported, is a manifestation of the multistep progression of CML.     

A case of localized Castleman's disease with systemic involvement: treatment and pathogenetic aspects

 A patient is presented who had Castleman's disease with constitutional symptoms, a palpable supraclavicular/axillar mass, and a microcytic anemia, among other laboratory abnormalities, including elevated levels of interleukin-6. Treatment consisted of irradiation of the involved area, with subsequent disappearance of all symptoms and normalization of the laboratory abnormalities. Iron kinetic studies demonstrated a hypoproliferative erythropoiesis, which normalized after radiotherapy. Hypoproliferative erythopoiesis could not be ascribed to serum inhibitors, since normal burst-forming units were observed in the absence or presence of autologous serum. The role of interleukin-6 in relation to Castleman's disease is highlighted. Received: 18 December 1995 / Accepted 27 March 1996