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- Patients and methods
We describe 21 patients with severe and life-threatening autoimmune cytopenias resistant to standard immunosuppression who were treated with the monoclonal antibody Campath-1H. Four patients had autoimmune neutropenia, four had autoimmune haemolytic anaemia, four had pure red cell aplasia, one had immune thrombocytopenia purpura (ITP), three had autoimmune haemolytic anaemia and ITP (Evan's syndrome), three had autoimmune pancytopenia (ITP, autoimmune neutropenia and autoimmune haemolytic anaemia), one had ITP (associated with acquired Glanzmann's disease) and autoimmune neutropenia, and one had ITP and red cell aplasia. Campath-1H was administered at a dose of 10 mg/d as an intravenous infusion for 10 d. Responses were seen in 15 patients, which were sustained in six. Relapse occurred in eight patients after Campath-1H treatment. Patients entering the study later, received cyclosporine after Campath-1H in an attempt to reduce the incidence of relapse. Three patients received a second course of Campath-1H; all responded but later relapsed. Fourteen patients are alive at a median of 12 months (range 4–61) after Campath-1H. Campath-1H represents an alternative therapeutic option for severe, refractory autoimmune cytopenias.
The majority of cases of autoimmune cytopenias, which includes immune thrombocytopenia purpura (ITP), autoimmune haemolytic anaemia, autoimmune neutropenia (AIN) and pure red cell aplasia, will respond to conventional immunosuppressive therapy with or without splenectomy. There is, however, a small group of patients with severe, refractory autoimmune cytopenias who fail to respond to conventional treatment or who have a chronic relapsing illness and suffer life-threatening haemorrhages, infections or anaemia as a result of their respective cytopenias. Further problems include the short- and long-term side-effects of corticosteroids, and the potential toxicity of immunosuppressive and cytotoxic agents such as vincristine, cyclophosphamide and azathioprine which can result in significant morbidity and sometimes mortality. It is in this subgroup of patients with severe life-threatening symptoms that a more aggressive approach, namely immunoablation, has recently been considered, for example using high-dose cyclophosphamide with autologous haemopoietic stem cell rescue (Schmitz et al, 1996). While this approach may be effective, it is also associated with a significant risk of morbidity and mortality.
An alternative and less toxic approach in these patients may be treatment with Campath-1H, a humanized IgG monoclonal antibody specific for the CD52 antigen and present on human lymphocytes and monocytes. The main effect of Campath-1H is on T cells and it results in a prolonged and profound depletion of the CD4 and CD8 subpopulations, particularly the CD4 population (Hale et al, 1990), and this might ‘reset’ the immune system without the need for total immune ablation. To sustain the effect and prevent relapse in the long term, subsequent treatment with a low dose of cyclosporine may be useful. In this study, we have assessed the potential of Campath-1H as an immunosuppressive agent in a series of 21 patients with severe refractory and life-threatening cytopenias.
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- Patients and methods
In this pilot study, we have shown that Campath-1H can induce clinical remission in some patients with severe, resistant and life-threatening autoimmune cytopenias who have failed to respond to conventional immunosuppression and/or splenectomy. The best responses were seen in patients with autoimmune neutropenia. A case report of patient 1 has previously been published (Killick et al, 1997). All other therapy for autoimmune neutropenia, such as prednisolone and G-CSF, could be withdrawn, apart from occasional G-CSF doses used by one patient despite always maintaining a neutrophil count > 0·5 × 109/l. Responses were also seen in some patients with red cell aplasia and autoimmune haemolytic anaemia. Although responses were seen in ITP that occurred in association with other cytopenias, relapses were frequent. Seven of the 21 patients died, reflecting the severity of the autoimmune cytopenias in this group of patients.
Campath-1H has been used extensively in the treatment of other autoimmune disorders such as rheumatoid arthritis (Isaacs et al, 1992), vasculitis (Mathieson et al, 1990; Lockwood et al, 1993) and Wegener's granulomatosis (Lockwood, 1998), in which it has been given as a short-term immunotherapy to replace long-term chemotherapy and/or allow tapering or withdrawal of corticosteroid therapy. It has also been used in bone marrow transplant recipients to prevent graft rejection and graft-versus-host disease (Hale & Waldman, 1994; Dickinson et al, 1997; Hale et al, 1998), and in the prevention and treatment of renal, liver and corneal graft rejection (Friend et al, 1989; Newman et al, 1995; Calne et al, 1998). The rationale behind the use of Campath-1H in this study was that T-lymphocytes are thought to play an important role in the pathogenesis of autoimmune cytopenias, as they are involved in the control of expansion of immunoglobulin-producing, auto-reactive B-lymphocyte clones. Along with improvement in the affected blood count, reduction or disappearance of the respective autoantibody was demonstrated after Campath-1H therapy. Campath-1H induced a profound lymphopenia. The B-lymphocytes recovered rapidly, the CD8+ T-lymphocytes more slowly, but a profound CD4+ lymphopenia persisted in all patients. In other reported studies in which Campath-1H has been used to treat patients with other autoimmune diseases, CD4+ T lymphopenia has persisted for several years (Brett et al, 1996).
Campath-1H, whether the first or second course, was well tolerated clinically apart from predictable first-day reactions. Despite the persistent and profound CD4+ T-lymphopenia, only one patient had a mild viral illness after treatment. Worsening thrombocytopenia has been previously reported in a patient with ITP treated with Campath-1G (Lim et al, 1993) and one patient with ITP in our study died on d +4 of Campath-1H treatment from intracranial haemorrhage, although this patient had severe generalized bleeding prior to Campath-1H. The use of Campath-1H in actively bleeding patients would therefore seem to be contraindicated. There were no cases of Epstein–Barr virus (EBV) lymphoproliferative disease, although this is less likely to occur than with patients who are treated with T lymphocyte-specific monoclonal antibodies. Similarly, there has been very low risk in bone marrow transplantation (BMT) recipients receiving Campath monoclonal antibodies (Hale & Waldmann, 1998). Two patients had tumour progression after treatment with Campath-1H. Although unproven, it is possible that these were the result of the immunosuppression caused by using Campath-1H. On relapse, additional autoantibodies were detected in two patients. This is a novel finding. The use of Campath-1H in the treatment of patients with multiple sclerosis has been associated with thyroid function abnormalities and antithyroid antibodies (Coles et al, 1995). It is possible that lymphocyte depletion caused by Campath-1H may remove cells which normally prevent autoimmunity, as seen in some experimental models (Saoudi et al, 1996). Alternatively, the appearance of new autoantibodies may be unrelated to the choice of treatment but rather to the nature of the disease.
In order to reduce the risk of relapse after Campath-1H treatment, most of our later patients received low-dose CSA after the course of Campath-1H. The rationale for this was based on the successful results reported in renal allograft recipients using peri-operative Campath-IH followed by low-dose CSA monotherapy to help prevent rejection and reduce the need for additional immunosuppressive drugs (Calne et al, 1998). Relapse of ITP after administration of the rat monoclonal antibody Campath-1G has been reported previously (Lim et al, 1993). The humanized monoclonal antibody, Campath-1H, has been shown in other studies to be less immunogenic, with the advantage that repeated courses may be given. Although we have not measured antiglobulin responses in our patients, re-treatment with Campath-1H was well tolerated and clinically effective.
Alternative therapeutic options to Campath-1H for the treatment of resistant autoimmune cytopenias include steroids, splenectomy, G-CSF for autoimmune neutropenia, cytotoxic immunosuppressants such as cyclophosphamide and azathioprine, and autologous peripheral blood stem cell transplantation. A high proportion of patients will respond to further courses of corticosteroids but many relapse on dose reduction. Long-term side-effects of corticosteroids, such as avascular necrosis and osteoporosis, may cause major morbidity. Splenectomy may be hazardous in severely thrombocytopenic patients and is associated with increased risk of overwhelming sepsis. Furthermore, response to splenectomy is often unpredictable in ITP and autoimmune haemolytic anaemia or patients may refuse to have a splenectomy (patients 6 and 15). G-CSF has been used successfully to treat autoimmune neutropenia but serious side-effects were observed in our patients, namely, chest pain, arrhythmias, sudden onset of agranulocytosis following initial response, and severe bone and muscle pains.
More recently, the use of high-dose immunosuppression with autologous peripheral blood stem cell (PBSC) rescue has been proposed for resistant autoimmune cytopenias as well as other autoimmune disorders. This may work by eliminating auto-reactive clones or by ‘resetting’ the immune system to induce tolerance towards self. While this approach may be effective, it is associated with a procedure-related mortality risk of 9% at 1 year (Potter et al, 1999; Tyndall et al, 1999). In view of the mortality observed in this series of patients, one could argue that autologous PBSC transplantation would have been an appropriate option, but there was only one case in whom death was possibly associated with Campath-1H itself. Furthermore, irradiation and high-dose cytotoxic immunosuppressive agents are associated with a risk of solid tumours and haematological malignancies later in life, in addition to infertility. Although the CD52 antigen is expressed on mature spermatozoa, it is not expressed on the developing gonadal tissue (Hale et al, 1993) and so infertility is not a predicted risk with Campath-1H antibody therapy.
We conclude that Campath-IH is an alternative and safe option in the treatment of patients with autoimmune cytopenias, allowing complete withdrawal of corticosteroid therapy in some cases. It may represent an effective alternative to cytotoxic immunosuppressive agents, stem cell transplantation and, possibly, splenectomy but further prospective studies are indicated to assess its efficacy more accurately in the different types of autoimmune cytopenias.