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1.
Ann Hematol ; 86(3): 191-7, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17123083

ABSTRACT

We describe 11 patients with severe refractory autoimmune cytopenias treated with the anti-CD20 monoclonal antibody rituximab. Six patients had autoimmune neutropenia (AIN), two had pure red cell aplasia (PRCA), one had AIN and autoimmune haemolytic anaemia, one had AIN and immune thrombocytopaenia purpura (ITP) and one had PRCA and ITP. Rituximab was administered at a dose of 375 mg/m(2) as an intravenous infusion weekly for 4 weeks. Six of eight patients with AIN and all three patients with PRCA did not respond. Two patients died: one with resistant AIN and autoimmune haemolytic anaemia died of pneumocytis pneumonia infection, and one with PRCA and ITP died of an acute exacerbation of bronchiectasis. Rituximab in AIN and PRCA appears to be less effective than Campath-1H when compared to historical data from our group. This supports the hypothesis that T cells may be important in the pathophysiology of AIN and PRCA.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Neutropenia/drug therapy , Red-Cell Aplasia, Pure/drug therapy , Adult , Aged , Anemia, Hemolytic, Autoimmune/drug therapy , Anemia, Hemolytic, Autoimmune/pathology , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Murine-Derived , Bronchiectasis/chemically induced , Drug Administration Routes , Drug Administration Schedule , Female , Humans , Immunologic Factors/administration & dosage , Immunologic Factors/adverse effects , Immunologic Factors/therapeutic use , Male , Middle Aged , Neutropenia/pathology , Pilot Projects , Pneumonia, Pneumocystis/chemically induced , Purpura, Thrombocytopenic/drug therapy , Purpura, Thrombocytopenic/pathology , Red-Cell Aplasia, Pure/pathology , Rituximab , Time Factors , Treatment Outcome
2.
Transfus Med ; 13(6): 377-86, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14651743

ABSTRACT

The clinical association between paroxysmal nocturnal haemoglobinuria (PNH) and aplastic anaemia (AA) has long been recognized. Haemolytic PNH, as confirmed by a positive Ham's test, can occur in the setting of AA, and conversely AA can be a late complication of PNH. With the development of sensitive flow cytometry to quantify the expression of phosphatidylinositolglycan (PIG)-anchored proteins on blood cells, a small PNH clone can now be detected in a large number of patients with AA at diagnosis. PIG-A gene mutations can also be demonstrated in some AA patients. In haemolytic PNH, there is always marrow suppression despite a morphologically cellular marrow. In vitro cultures show markedly diminished proliferative capacity in both short-term and long-term marrow cultures, similar to that seen in AA. A similar autoimmune process, through the T-cell cytotoxic repertoire, is probably responsible for the pathogenesis of both AA and PNH. PIG-deficient cells may be resistant to immunological attack by autoreactive cytotoxic T cells, because they lack PIG. They are also more resistant to apoptosis than the PIG-normal cell population. This results in the selection of the PIG-deficient clone, in contrast to the PIG-normal stem cells which possess the PIG anchor and hence are targeted and depleted by the autoreactive T cells.


Subject(s)
Anemia, Aplastic/pathology , Hematopoietic Stem Cells/pathology , Hemoglobinuria, Paroxysmal/pathology , Adult , Anemia, Aplastic/immunology , Apoptosis , Autoimmune Diseases/pathology , Bone Marrow/pathology , Child , Clone Cells/pathology , Glycosylphosphatidylinositols/physiology , Hemoglobinuria, Paroxysmal/genetics , Hemoglobinuria, Paroxysmal/immunology , Humans , Membrane Proteins/deficiency , Membrane Proteins/genetics
3.
Ann Hematol ; 81(7): 378-81, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12185507

ABSTRACT

We report the outcome of nine unrelated bone marrow transplants performed for acquired severe aplastic anaemia at a single centre. Six patients received transplants from fully matched donors. Three donor/recipient pairs were mismatched, two at a single allele on high resolution typing. Pre-transplant conditioning consisted of cyclophosphamide and in vivo Campath-1 monoclonal antibody. One patient also received total body irradiation (TBI), and another patient with a coexisting paroxysmal nocturnal haemoglobinuria (PNH) clone received additional busulphan. Cyclosporin A was given for 12 months as prophylaxis against graft-versus-host disease (GVHD). Six of nine patients are alive and transfusion independent with a mean follow-up of 24 months (range: 1.5-94). All six patients who received fully matched transplants are alive; the three who received mismatched grafts died. Four long-term survivors developed autologous haematological recovery following rejection of their grafts. Acute GVHD grade II+ occurred in two patients. We highlight the importance of high-resolution HLA typing, including Cw matching in reducing the incidence of graft rejection and GVHD, resulting in improved survival in our patient group. This study also shows that autologous recovery with long-term survival can occur following non-irradiation conditioning regimens.


Subject(s)
Anemia, Aplastic/surgery , Bone Marrow Transplantation , Tissue Donors , Adolescent , Adult , Anemia, Aplastic/blood , Bone Marrow Transplantation/adverse effects , Child , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/mortality , Humans , Male , Mycoses/etiology , Mycoses/mortality , Recovery of Function , Severity of Illness Index , Survival Analysis
4.
Stem Cells ; 18(6): 428-34, 2000.
Article in English | MEDLINE | ID: mdl-11072031

ABSTRACT

It has previously been shown that patients with aplastic anemia (AA) have a stem cell defect both of proliferation and differentiation. This has been shown by long-term bone marrow (BM) culture, long-term initiating cell assays, and committed progenitor assays. We present, for the first time, data on megakaryocyte (Mk) colony formation from purified BM CD34(+) cells from patients with AA. The results are compared with those from normal controls and from patients with paroxysmal nocturnal hemoglobinuria (PNH) and the myelodysplastic syndromes (MDSs). Those treated for AA had previously received immunosuppression (antithymocyte globulin and/or cyclosporin). No patients had received bone marrow transplantation. A total of 13 AA patients (five untreated, eight treated), six PNH, six MDS, and 13 normal donors were studied. BM CD34(+) cells were purified by indirect labeling and then cultured in a collagen-based Mk assay kit (MegaCult-C, StemCell Technologies). The cultures were fixed on day 12, and the Mk colonies were identified by the alkaline phosphatase anti-alkaline phosphatase technique using the monoclonal antibody CD41 (GP IIb/IIIa). The slides were scored for Mk colony-forming units (CFU-Mks) (3-20 and >20 cells), Mk burst-forming units (BFU-Mks) (>50 cells), and mixed colonies. The results show that total Mk colony formation in AA was significantly lower than in normal donors (p<0.0001), both in untreated patients/nonresponders to treatment (p = 0.0001) and in complete/partial responders (p<0.002). There was no significant difference in Mk colony formation in treated and untreated patients (p = 0.05). Patients with AA had a lower total colony formation than PNH patients (p = 0.0002). PNH patients exhibited lower colony formation than normal controls (p = 0.03), as shown by MDS patients, although the considerable number of variables resulted in a lack of statistically significant difference from normal controls (p = 0.2). We have now shown that Mk colony formation from purified BM CD34(+) cells is significantly reduced, supporting previous evidence that AA results from a stem cell defect.


Subject(s)
Anemia, Aplastic/blood , Hematopoietic Stem Cells/cytology , Hemoglobinuria, Paroxysmal/blood , Megakaryocytes/cytology , Myelodysplastic Syndromes/blood , Cell Differentiation , Cell Division , Cell Separation , Humans
5.
Br J Haematol ; 93(4): 884-7, 1996 Jun.
Article in English | MEDLINE | ID: mdl-8703821

ABSTRACT

With the increasing use of chemotherapy for many different primary malignancies, secondary or therapy-related acute myeloid leukaemias (AML) and myelodysplastic syndromes (MDS) are becoming more common. The risk of developing sAML has been estimated to be between 2% and 10%, depending upon the type, duration and dosage of previous therapy (Michels et al, 1985; Shulman, 1993; Robinson & Mertens, 1993; Ballen & Antin, 1993). It is therefore one of the most serious long-term complications of current cancer treatment and is likely to increase as longer survival rates for the primary tumour are achieved. An increasing range of drugs have been reported to cause sAML, including the alkylating agents, the epipodophyllotoxins and the anthracyclines, both as single agents and in combination (Pedersen-Bjergaard & Philip, 1991; Pedersen-Bjergaard & Rowley, 1994). We report two cases of secondary AML in which platinum compounds were the sole prior chemotherapy.


Subject(s)
Antineoplastic Agents/adverse effects , Carboplatin/adverse effects , Cisplatin/adverse effects , Leukemia, Myeloid/chemically induced , Acute Disease , Adenocarcinoma/drug therapy , Adult , Fatal Outcome , Female , Humans , Middle Aged , Ovarian Neoplasms/drug therapy
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