Treatment of patients with refractory rheumatoid arthritis with extracorporeal protein A immunoadsorption columns: a pilot trial.

OBJECTIVE: To evaluate the safety and effectiveness of extracorporeal immunoadsorption with protein A (PROSORBA) columns in the treatment of refractory rheumatoid arthritis (RA). METHODS: Eleven patients with refractory RA were enrolled in an open prospective trial of 24 weeks' duration. Nine patients received 15 treatments over a 12-week period, 1 patient received 15 treatments over a 15-week period, and 1 patient received 12 treatments over a 9-week period. RESULTS: Using the composite criteria of Paulus, et al, 9 patients met the > or = 50% criteria when tested at Week 13, while 4 and 2 patients met the > or = 50% and > or = 20% criteria, respectively, when tested at Week 24. In addition, most of the clinical variables in the 9 responders at Week 13 had significantly improved (p < 0.05); 8 of these responders were able to continue for the entire 24-week study without a change in their arthritic medications, and 2 met the American College of Rheumatology criteria for clinical remission at Weeks 12, and 28 and have remained in remission for 6 and 5 months, respectively. Treatment associated side effects were of short duration and resolved without sequela. Four patients became symptomatically anemic during the treatments. CONCLUSION: Our preliminary study suggests that extracorporeal immunoadsorption therapy with protein A columns was well tolerated and may be effective in the treatment of RA. Further expanded and controlled trials are indicated to explore this new therapeutic modality.

Treatment of cancer chemotherapy-associated thrombotic thrombocytopenic purpura/hemolytic uremic syndrome by protein A immunoadsorption of plasma.

BACKGROUND: Chemotherapy-associated thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (C-TTP/HUS) is a condition involving thrombocytopenia, microangiopathic hemolytic anemia, and progressive renal dysfunction that develops in 2-10% of patients with a history of malignant neoplasms treated with certain chemotherapeutic agents. Pathogenesis of the disease may depend on the following: (1) generation of endothelial lesions in the kidney microvasculature, resulting from drug toxic effects and/or generation of small soluble circulating immune complexes (CIC), and (2) generation of autoantibodies and/or CIC that trigger aggregation and deposition of platelets around the lesions. METHODS: Extracorporeal immunoadsorption treatment of plasma (PROSORBA columns, IMRE Corporation, Seattle, WA) to remove immunoglobulin G and CIC was evaluated in 55 patients for the potential to induce significant clinical benefits (increase in platelet count, decrease in hemolysis, stabilization of renal function) and longer survival. RESULTS: Response to therapy was achieved in 25 of 55 patients examined. Response was associated with an estimated 1-year survival rate of 61%, as compared with an estimated survival rate of only 22% in those who did not respond (P = 0.0001). Patients whose malignant neoplasms were in complete or partial remission at the time of development of C-TTP/HUS had a significantly higher estimated 1-year survival rate (74%) as compared with a historic control group of patients receiving other treatments (22%, P = 0.0161). Clinical responses were correlated with normalization of serum levels of CIC and complement components C3c and C4. There were no side effects associated with 75% of treatments. Immunoadsorption therapy was associated with generally mild to moderate manageable side effects, such as fever, chills, nausea/vomiting, respiratory symptoms, pain, hypertension, and hypotension, which were reported in 25% of procedures. CONCLUSIONS: This multicenter study establishes protein A immunoadsorption as an effective and safe treatment for cancer chemotherapy-associated TTP/HUS, an otherwise fatal disease.

Experience with protein A-immunoadsorption in treatment-resistant adult immune thrombocytopenic purpura.

Extracorporeal immunoadsorption of plasma to remove IgG and circulating immune complexes (CIC) was evaluated as a therapy for adults with treatment-resistant immune thrombocytopenic purpura (ITP). Seventy-two patients with initial platelet counts less than 50,000/microL who had failed at least two other therapies were studied. They received an average of six treatments of 0.25 to 2.0 L plasma per procedure over a 2- to 3-week period using columns of staphylococcal protein A-silica (PROSORBA immunoadsorption treatment columns; IMRE Corp, Seattle, WA). The treatments caused an acute increase in the platelet count to greater than 100,000/microL in 18 patients and to 50,000 to 100,000/microL in 15 patients. The median time to response was 2 weeks. Responses were transient (less than 1 month duration) in seven of those patients (10%), but no additional relapses were reported over a follow-up period of up to 26 months (mean of 8 months). Clinical responses were associated with significant decreases in specific serum platelet autoantibodies (including anti-glycoprotein IIb/IIIa), platelet-associated Ig, and CIC. Thirty percent of treatments were associated with transient mild to moderate side effects usually presenting as a hypersensitivity-type reaction. Continued administration of failed therapies for ITP, which always included low-dose corticosteroids (less than or equal to 30 mg/d), had no demonstrable influence on the effectiveness of immunoadsorption treatment but did depress the incidence and severity of side effects. The degree of effectiveness of protein A immunoadsorption therapy in patients with treatment-resistant ITP is promising and further controlled studies in this patient population are warranted.

Use of protein A immunoadsorption as a treatment for thrombocytopenia in HIV-infected homosexual men: a retrospective evaluation of 37 cases.

Thirty-seven HIV-infected homosexual men with thrombocytopenia (less than 100 x 10(9)/l) received protein A immunoadsorption treatments to remove platelet-sensitizing immunoglobulin (Ig) G and circulating immune complexes (CIC) from plasma. Patients received an average of six treatments each, consisting of 250 ml plasma over a 3-week period. Clinical improvement in hemorrhagic symptoms associated with substantial increase in platelet counts was achieved in 18 patients. These responses were maintained over a median follow-up period of more than 7 months in 14 evaluable patients who were not lost to follow-up (three patients relapsed in 2 weeks and one received another therapy). Generally, moderate transient treatment-related side-effects included fever, musculoskeletal pain, chills and nausea. A transient serum sickness-like reaction was observed in seven patients, leading to termination of treatment in two. Clinical responses were associated with significant decreases in levels of platelet-sensitizing Ig, including CIC. Stimulation of broadly cross-reactive anti-antigen-binding fragment [F(ab)2], antibodies contributed to these responses. Protein A immunoadsorption is an effective alternative treatment for HIV-associated thrombocytopenia.

Reduction in platelet-binding immunoglobulins and improvement in platelet counts in patients with HIV-associated idiopathic thrombocytopenia purpura (ITP) following extracorporeal immunoadsorption of plasma over staphylococcal protein A-silica.

Platelet-directed antibodies and circulating immune complexes (CIC) were removed from plasma of patients with human immunodeficiency virus (HIV) infection and idiopathic thrombocytopenic purpura (ITP) by extracorporeal immunoadsorption using columns of Staphylococcal protein A-silica (Prosorba columns). In addition, stimulation of a broadly cross-reactive anti-F(ab')2 antibody response was observed. These antibodies also appeared to play a role in the additional removal of platelet-directed immunoglobulins (Igs) and CIC from plasma. Removal of these components from plasma was associated with diminishing levels of antibodies and CIC on patient platelets and significant increases in platelet counts. Extracorporeal immunoadsorption of IgG and CIC from plasma is a beneficial new treatment modality for HIV-associated ITP.

Protein A immunoadsorption therapy in HIV-related immune thrombocytopenia: a preliminary report.

Nine homosexual patients with immune thrombocytopenia were treated with autologous plasma that had been perfused over silica-immobilized Staphylococcus aureus protein A (SpA). Pretreatment platelet counts ranged from 10,000 to 98,000 cells/mm3 (mean: 54,000 cells/mm3). Six patients responded to therapy. Platelets increased by a mean of 95,000 cells/mm3 (p less than 0.007) and reached normal levels (greater than 150,000 cells/mm3) in four patients. Increased platelet counts are presently sustained in these four individuals after 5 months of follow-up. Increases in platelet counts significantly correlated with decreases in platelet-associated IgG (PAIgG), platelet-directed IgG (PDIgG), and immune complexes (CIC). PAIgG and PDIgG declined by a mean of 67% (p less than 0.003) and 58% (p less than 0.007), respectively. CIC decreased by a mean of 37% (p = 0.02). Complement was concomitantly activated in all four examined patients. C3a and C5a increased 23-fold and 2.6-fold, respectively, while total hemolytic complement decreased by 50%. Activated complement components and removal of CIC and IgG thus may contribute to the platelet-enhancing activity of SpA immunoadsorption therapy.

Treatment of astrocytoma with a 5-day cisplatin infusion.

Although cisplatin may have intrinsic activity against astrocytoma, limited penetration into the central nervous system may severely curtail delivery of adequate amounts of drug to the tumor. In an attempt to increase the dose of delivered drug without markedly increasing toxicity, cisplatin was administered by 5-day continuous intravenous infusion at a dose of 28 mg/m2/day (total dose 140 mg/m2) to 15 evaluable patients (5 with astrocytoma Grade III and 10 with astrocytoma Grade IV). Median age was 39 years, median Karnofsky Performance Status was 80%, and all patients had been previously treated with other modalities. One patient (7%) achieved Partial Response as demonstrated by increased strength of paretic extremities, increased Karnofsky Performance Status, and decrease of enhancing tumor mass on CT scan. Although nephrotoxicity was minimal, nausea and vomiting (usually mild) was seen in 14 patients. Myelosuppression was also common (anemia in 7 patients, leukopenia in 4 patients and thrombocytopenia in 3 patients). Ototoxicity was seen in 5 patients and may represent a combined modality toxicity with prior cranial radiotherapy. Routes and schedules which allow a higher peak serum concentration of cisplatin (such as subselective intracerebral artery infusion) may be necessary to achieve greater central nervous system drug penetration and to maximally exploit cisplatin in the treatment of astrocytoma.

Monoclonal antibody T101 in T cell malignancies: a clinical, pharmacokinetic, and immunologic correlation.

Eight patients with cutaneous T cell lymphomas (CTCL) and five with various other T cell malignancies were treated with mouse monoclonal antibody (MoAb) T101. Doses of 1 to 500 mg were administered weekly over a two-hour period and resulted in one complete remission (convoluted T cell lymphoma) and one partial remission (CTCL). Remission duration was 6 weeks and 3 months, respectively. Frequent toxicities were pruritus, hives, flushing, and shortness of breath. Supraventricular arrhythmias and blood pressure instability were also observed. Complete targeting of peripheral blood T cells was achieved with 1 mg of MoAb in the nonleukemic patients (WBC less than 10,000/microL), and free, bioavailable antibody was present at the next (10-mg) dose level. Even higher doses resulted in substantial antibody excess that persisted for as long as 6 weeks. Serum concentrations of MoAb decreased with increasing number of peripheral blood T cells, and 25 to 35 mg of T101 were required for induction of antibody excess in leukemic patients. Excess antibody induced antigenic modulation, which was of consequence only if MoAb excess persisted to the next treatment. In the original treatment, the rapidly administered MoAb was able to target and remove peripheral blood T cells before the development of antigenic modulation. Antimouse antibodies developed in three patients. Their presence rendered further therapy ineffective and was associated with an anaphylactic reaction in one patient. Development of these antibodies could not be predicted by lymphoproliferative assays. In these assays, however, the T101 protein strongly stimulated the mononuclear cells of the patient who reached the only complete remission of this trial. Immunologic stimulation by the MoAb thus might have played a role in this patient's antitumor response. In summary, therapy with MoAb T101 was specific but only modestly efficacious. Rapid infusion of nonmodulating doses of antibody provided excellent targeting and removal of peripheral blood T cells and might be a valid approach in future trials with immunoconjugated T101.

Staphylococcal Protein A column: correlation of mitogenicity of perfused plasma with clinical response.

Eleven patients with advanced breast cancer and four with astrocytoma were treated with plasma perfused over columns containing staphylococcal Protein A (SPA). Doses of 5 to 20 mg of SPA were bound to collodion charcoal particles, and this treatment resulted in partial remissions in one patient with astrocytoma and in two patients with breast cancer. Remission duration was 6 wk to 6 mo. Resolution of lymphadenopathy and a decrease in carcinoembryonic antigen were noted in an additional two breast cancer patients. Systemic reactions to infused plasma consisted of fever, chills, and rigors. In brain cancer patients, increased intracranial pressure was also noted. A mitogenic substance was generated in plasma of 11 patients after it was perfused over the SPA charcoal matrix. The mitogenic material induced lymphoproliferation comparable to concanavalin A and required the presence of SPA on the collodion charcoal but was not due to leakage of SPA from the column during plasma perfusion. Of considerable significance was that only patients whose column perfused plasma contained this mitogenic activity exhibited systemic reactions, and five of these patients obtained antitumor responses. This striking correlation implies that the mitogenic factor is an active component of SPA therapy. The ability to demonstrate mitogenicity in column perfused plasma might also be useful for selecting patients amenable to SPA therapy. These findings attest to the therapeutic value of this mode of treatment and provide an initial definition of a mediator of SPA antitumor activity.

Staphylococcal protein A immunoadsorptive column induces mitogenicity in perfused plasma.

A Phase I trial of therapy with the staphylococcal protein A immunoadsorptive column was conducted in six patients with advanced breast or brain cancer. Four of the patients reacted strongly to the therapy with high fever, chills, and rigors. The plasma of these four patients after perfusion over the column was strongly mitogenic to normal lymphocytes. This mitogenicity apparently was dependent on the amount of protein A on the matrix; small attached doses caused mitogenicity, while higher doses also induced clinical symptoms. Mitogenicity was not due to protein A leached from the column, as determined by heat-inactivation experiments. From these data it appears likely that the mitogenic plasma component generated by perfusion of the plasma over a protein A matrix is responsible, at least in part, for the immunomodulatory activity of the staphylococcal protein A immunoadsorptive column.