Journal of Clinical Apheresis 5206-212 (1990)

Therapeutic Plasmapheresis and Protein A lmmunoadsorption in Malignancy: A Brief Review Sucha Nand and Robert Molokie Section of HematologylOncology, Department of Medicine, Loyola University Stritch School of Medicine, Maywood, Illinois Plasmapheresis is being used with considerable frequency in the management of malignant and non-malignant disorders. More recently, staphylococcal Protein A immunoadsorption has been employed in similar clinical situations. In patients with malignancy, plasmapheresis has been shown to produce alterations in plasma proteins, decrease circulating immune complexes, remove “specific” and “non-specific” blocking factors, change immune reactivity, and affect monocyte function. Partial responses have been reported in a small number of patients with carcinoma of lung, colon, and breast following plasmapheresis. In addition, there are reports of favorable responses in patients with melanoma, head and neck tumors, lymphomas, leukemias, and Kaposi’s sarcoma in acquired immune deficiency. All these responses were partial and brief, and the treatment did not alter the course of the disease. Plasmapheresis has been useful in the management of hyperviscosity and occasionally of paraneoplastic syndromes. It may also have a role in the treatment of thrombotic thrombocytopenic purpura associated with mitomycin-C therapy. Protein A immunoadsorption, by which circulating immune complexes are selectively removed, can activate the complement system, increase blastogenic responses, and increase the natural killer cell activity. It has been shown to produce partial responses in breast and colon cancer, as well as Kaposi’s sarcoma in acquired immune deficiency. It may have a useful role to play in the management of mitomycin-C-associated thrombotic thrombocytopenic purpura. Both plasmapheresis and Protein A immunoadsorption should be considered investigational interventions at this time. Toxicity of plasmapheresis, though uncommon, can be serious and may rarely be fatal. Toxicity of Protein A immunoadsorption is mild, consisting mainly of influenza-like symptoms and rash.

Key words: plasma proteins, immune complexes, mitomycin-c

INTRODUCTION

Plasmapheresis, initially carried out by Felig and Abel [ 1,2] in 1909 and 1914, has become increasingly popular

as a therapeutic modality. In 1982, about 80,000 plasma exchange treatments were carried out in North America [3]. The cost of each treatment varied between $400 and $1,600 [ 3 ] . The range of medical illnesses treated by plasmapheresis is very wide and includes hyperviscosity syndromes, immune hemolytic anemias and thrombocytopenias, thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, my asthenia gravis, hypercholesterolemia, Guillain-Barre syndrome, rheumatoid arthritis, systemic lupus, and heparin-associated thrombocytopenia with thrombosis and malignancies [4- 121. The purpose of this communication is to critically review the use of plasmapheresis in malignant disease for its therapeutic effects. Plasmapheresis can be performed by membrane filtration, centrifugation, or flat- and hollow-fiber techniques. The plasma is removed from the whole blood during extracorporeal circulation. Since plasmapheresis removes plasma and thus, its constituents, its efficacy will depend upon the amount of the target plasma constituent 0 1990 Wiley-Liss, Inc.

removed. Hence it is necessary to understand the kinetics of plasma exchange to determine the optimal volume and frequency of the treatments. This has been calculated by Calabrese [ 131 and associates as follows: Step 1

The clearance rate of a substance, when considered as a function of the volume alone, can be calculated as: r =

volume of exchange per hour plasma volume

Step 2

If plasma volume is considered a closed system, the concentration of substance “X” after time “t” of plasmapheresis is given by the equation: Xt

=

Xoe-“

Received for publication May 22, 1989; accepted Decembcr 5 , 1989. Address reprint requests to Dr. Sucha Nand, Section of Hematology/ Oncology, Department of Medicine, Loyola University Stritch School of Medicine, 2160 South First Avenue, Maywood, IL 60153.

Plasmapheresis and Protein A Immunoadsorption in Cancer

Here, Xo is the initial concentration of X and r is the fractional rate of exchange calculated by step 1. If the synthesis and catabolism of substance X are equal, then each plasmapheresis treatment, in which the volume exchanged equals patient’s total plasma volume, will remove 50-60% of an intravascular substance. Four to five such treatments over a period of 7-10 days are generally believed to be adequate for therapeutic purposes [ l l]. The replacement fluids utilized after plasma is removed are not standardized and vary from study to study and at times depend upon the underlying disease. (In TTP, the replacement fluid must be plasma [9,11],) Fresh-frozen plasma, human albumin, saline, and various combinations of these have been used. There is little information regarding the effects of replacement fluids on the disease process under study or its pathophysiology. This also makes comparisons between studies more difficult. Another, more recent, approach has been the specific extracorporeal removal of IgG and IgG-associated circulating immune complexes (CICs) from plasma by using staphylococcal Protein A immunoadsorbtion. The patient plasma is passed over columns containing a silica matrix and covalently attached, highly purified staphylococcal Protein A . Protein A has a greater affinity for immune-complexed IgG than monomeric IgG. The exact basis for this difference is not known, but it is believed that antigen binding causes conformational changes in the Fc portion of the IgG. PATHOPHYSIOLOGIC EFFECTS OF PLASMAPHERESIS AND PROTEIN A IMMUNOADSORPTION

In benign disorders, the beneficial effects of plasmapheresis occur through a variety of mechanisms 14121, some of which are proven [4-6,9]. These include removal of toxins (mushroom poisoning) [41, paraproteins (hyperviscosity syndromes) [ 5 ] ,allo-antibody (Rh allo-immunization in pregnancy) [6], auto-antibody (myasthenia gravis) [7], and of circulating immune complexes (systemic lupus erythematosis) [SJ; replenishment of a deficient plasma factor (TTP) [9]; and placebo effect (rheumatoid arthritis) [lo]. In most of the above examples, clinical results can be correlated with a measurable biochemical alteration, i.e., decreased levels of paraproteins paralleling improvement in serum viscosity and clinical findings; while in others, i.e., TTP, this relationship is speculative. Malignancy induces complex changes in host systems and some of these become potential targets for therapy with plasmapheresis. These include 1) alterations in plasma proteins 114- 171, 2) presence of circulating im-

207

mune complexes [ 18-26], 3) specific and “non-specific blocking factors” [ 16,27-291 and 4 ) changes in immune reactivity 130-391 and in monocyte function [38]. We will discuss each of these briefly. Plasma Proteins

In both experimental and human malignancy, levels of certain plasma proteins have been shown to be elevated while others have been lowered [ 14-17]. In a study [29] which eventually included 232 patients with breast cancer, gastrointestinal adenocarcinomas, cancer of the ovary, cancer of lung and melanoma; levels of alpha 1, alpha 2, and beta globulins: alpha 1 antitrypsin; ceruloplasmin; haptoglobin; orosomucoid; and IgA were elevated. On the other hand, levels of albumin, prealbumin, and alpha-2 HS-glycoprotein were depressed. The precise mechanism of these changes is not known but the degree of elevation or fall in the protein levels generally parallels the tumor burden and decreased in vitro reactivity of the host lymphocytes against phytohemagglutinin (PHA) and dinitrochlorobenzene (DNCB). Circulating Immune Complexes

Circulating immune complexes (CICs) can be demonstrated in 62 to 90% of the patients with advanced melanoma after a single sampling of their plasma [22]. In contrast, 48% patients with ovarian carcinoma and 24% patients with breast cancer demonstrated presence of CICs [22-24]. Isolation and characterization of CICs has been successfully done from patients with breast and lung cancers and melanoma [23]. These have been shown to consist of tumor antigens and antibodies against them. The CICs can vary widely in size and composition. The concentration of immune complexes increases with increasing tumor burden 122-261. The CICs are capable of inhibiting in vitro lymphocyte reactivity and can elicit a suppressor T lymphocyte response 1391. Elevated CICs have also been associated with poor prognosis, with one study showing an inverse relationship between the CIC levels and survival in lung cancer patients [26]. If the ratio between tumor antigen and antibody concentration changes in cancer patients (i.e., after successful therapy), it can also affect the biochemical nature of the CICs and may lead to development of TTP-like syndromes [251. Blocking Factors

In 1969, Hellstrom and associates proposed the concept of “specific blocking factors” in animals and humans with cancer 1271. These specific blocking factors consisted of tumor antigens, antigen antibody complexes, and a presumed T-cell-derived suppressing factor. It was suggested that the presence of these specific factors helps the tumor escape the host immune system

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[28]. Over the last 10 years, some investigators have proposed the concept of “non-specific blocking factors.” This was based on studies on patients with metastatic cancer who showed partial objective responses to plasmapheresis [ 16,291. The responders, when compared to non-responders, showed a greater fall in their alpha 1 and alpha 2 globulins, alpha 1 antitrypsin, haptoglobin, orosomucoid, IgA, and IgM levels. The differences between the responders and non-responders were not statistically significant. Nevertheless, these findings prompted the suggestion that plasmapheresis removed the “non-specific blocking factors” which led to clinical responses. The non-specific blocking factors have remained a concept and there is no definite evidence for their presence or their role in cancer pathology. Alterations in Immune Reactivity Following Plasmapheresis and Protein A lmmunoadsorption

Since the true relationship between malignant disease and the immune system is not known, the changes in the immune system following plasmapheresis must be interpreted with a great deal of caution. In vitro immune reactivity, as measured by PHA and DNCB [17, 321 responses, has been shown to improve following plasmapheresis. Similarly, antibody-dependent cellmediated cytotoxicity against melanoma cells was reported to increase after repeated plasmapheresis [34]. Another study [35] in which immune parameters were measured before, during, and after plasmapheresis and related to tumor size in a patient with melanoma showed improvement in helper/suppressor T lymphocyte ratio and an increase in NK cytotoxicity and objective tumor response with plasmapheresis. These changes were, however, short-lived, with the reversal of immune changes to baseline accompanied by disease progression in 10 weeks. Mobilization and function of monocytes appear to improve with plasmapheresis [38]. The mechanism by which the plasmapheresis improves immune reactivity and phagocytic functions is not clear. It is possible that these are effected through removal of immune complexes which, as mentioned earlier, can influence lymphocyte reactivity at different levels. Plasma fibronectin levels fall with plasmapheresis [40] but return to pretreatment levels in 2-3 days regardless of whether plasmapheresis is continued or not. The passage of plasma over Protein A columns has been shown to 1) remove CICs, 2) activate the complement system, and 3) release free antibody from the CICs [41-461. Following the Protein A immunoadsorption, there is an increase in the T helper/suppressor ratio, an increase in the blastogenic responses, and augmented NK cell activity [41,42,44-461. There is also a significant increase in the antibody against tumor-

TABLE I. Immunologic Changes Following Plasmapheresis and Protein A Immunoadsorption Plasmaoheresis Fall in alpha 1 antitrypsin haptoglobin, orosomucoid, and IgA and IgM levels Increased blastogenic responses Increased helperisuppressor T lymphocyte ratio Increased NK cell activity Decreased fibronectin levels (temporary)

Protein A immunoadsomtion Activation of complcment system Increased blastogenic responses Increased helperisuppressor T lymphocyte ratio Increased NK cell activity

associated antigens [46] (Table I). Stimulation of immune cellular activity is seen 1 to 3 hours post treatment. During the first one to three treatments, cells of granulocytic and macrophage lineage show the greatest increase. During treatments 2 to 4, the lymphocytic response predominates [46]. Enhanced antibody response to a glycolipid antigen associated with breast adenocarcinoma following extracorporeal immunoadsorption with Protein A has been shown [45,46]. PLASMAPHERESIS AND PROTEIN A IMMUNOADSORPTION AS THERAPEUTIC MODALITIES IN CANCER

Even though plasmapheresis has been used extensively in various malignancies, there are only a few reports (Table 11) of its use in a consistent manner or in the same histology [16,17,47,48]. Its most proven value is in the management of hyperviscosity syndromes associated with multiple myeloma and Waldenstrom’s macroglobulinemia [49-5 11. Up to 80% of the M protein can be removed by this treatment, which may help prevent serious morbidity. In addition, plasmapheresis has been used to successfully treat renal failure, coagulopathy , polyneuropathy , priapism, and corneal crystal formation occurring as complications of multiple myeloma [52561. Recently, with newer techniques, it has become possible to selectively remove the M protein in myeloma patients [49]. Wahlin and colleagues [48] have reported that addition of plasmapheresis to combination chemotherapy may prolong survival in multiple myeloma (Table 11). Patients receiving melphalan, cyclophosphamide, BCNU, vincristine, and prednisone along with plasmapheresis had a median survival of 63 months, compared to 23 months for those who received melphalan, prednisone, and plasmapheresis and 9 months for those receiving melphalan and prednisone alone. The median survival for the first group was significantly better than the other two but there was no statistical differ-

Plasmapheresis and Protein A Immunoadsorption in Cancer

209

TABLE 11. Therapeutic Plasmapheresis and Protein A Immunoadsorption in Malignancy: Results of Reported Experience No. of patients 23 16 6 5Ib

87

Plasmapheresis therapy 4 liters biweekly 3-liter single treatment 2 liters, 2-3 times a week a) 3 liters/day for 3 days; repeat every 5 weeks (25 pts) b) Same as above (9 pts) c) No plasmapheresis (23 pts) Protein A immunoadsorption weekly for 12 weeks

Partial response rate

Duration of response

Median survival

Ref.

Multiple

8/23 (35%)

NA"

6.5 mo

[16]

Multiple

0

NA

NA

~ 7 1

Head & neck Multiple myeloma

216 (33%)

NA

79 days

[47]

-

NA

61 mo

[48]

-

NA

23 mo

-

NA

9 mo

NA

NA

Histology

Multiple myeloma Multiple myeloma Multiple

21 (24%)'

[721

"NA = not available. ba) These patients received chemotherapy with melphalan, cyclophosphamide, vincristine, carmustine, and prednisone, in addition to plasmapheresis; b) these patients received melphalan and prednisone with plasmapheresis. c) these patients received chemotherapy with melphalan and prednisone but no plasmapheresis. Response rates could not be judged precisely because of artificial lowering of paraproteins in groups a and b. 'Some of the responses were minimal

ence in survival between the second and third groups. Thus the advantage of the first group may have been from the additional chemotherapy rather than plasmapheresis. Other reports on the uses of plasmapheresis in malignancy [ 16,17,47] have been on patients with advanced disease of different histologies. The paper by Israel and associates reported the results on 23 evaluable patients with metastatic breast, lung, colon, and thyroid carcinomas; melanoma; and other tumors. Eight of these patients (35%) showed partial responses. All the responses were of short duration with relapses occurring during or soon after plasmapheresis therapy. The median survival for the entire group was 6.5 months. The experience of others has been very similar. There is no evidence that plasmapheresis alters the clinical course of the underlying disease. There are numerous reports of beneficial effects of plasmapheresis in oral cancer, lymphomas, leukemias, paraneoplastic syndromes like Eaton-Lambert or cerebellar degeneration in lung cancer, and Kaposi's sarcoma in acquired immune deficiency [52,57-591. All of these are either single case reports or had small numbers of patients. The responses were, as a rule, minimal and temporary. In another paper [60], tumor sensitivity to chemotherapy was shown to be enhanced by plasma-

pheresis. Plasmapheresis has also been shown to provide symptomatic relief in cryoglobulinemia associated with lymphoma [61]. One area of potential utility of plasmapheresis is in the management of TTP-like syndromes associated with malignancy or mitomycin C therapy [25,62-651. The TTP-like syndrome appears after clinical response to therapy has been shown. It is believed that the reduction in the tumor mass leads to the disappearance of preexisting antigen excess, allowing formation of soluble antigen-antibody complexes which in turn are responsible for the development of the microangiopathic syndrome [25]. In most reports of tumor-associated TTP, plasmapheresis was of clinical benefit (62,631. However, in the TTP syndrome associated with mitomycin C therapy, all four patients in one report 1631 but only 1 out of 12 in another report [64] responded to plasmapheresis. In 1984, a national registry for [65] cancer-associated hemolytic uremic syndrome was established at Georgetown University. By 1988, 85 patients had been registered. In 84 of these patients, mitomycin had been used. Fifty percent of the patients died within 8 weeks of diagnosis. Thirty-seven patients received plasmapheresis and 11 of these (30%) showed improvement. Ten of 21 patients who received staphylococcal Protein A im-

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munoadsorption improved. The statistical analysis tended to favor the Protein A treatment in this study but the results of this study must be treated with extreme caution as patients were highly selected and many other therapies (e.g., steroids) had also been employed. Protein A has also been reported to be of benefit in two patients (with squamous cell carcinomas of head and neck region) who developed hemolytic uremic syndrome after treatment with cisplatin [66]. Protein A immunoadsorption has not been studied extensively in malignancy. Antitumor effects of this therapy, however, have been shown in animal and human tumors [67-721. In humans, it has been shown to produce partial or minimal responses in breast cancer, Kaposi’s sarcoma, and colon cancer [72]. Smaller numbers of patients with other malignancies have also been reported to respond. The multicenter trial reported by Messerschmidt [72] and colleagues is the largest clinical study reported on the use of Protein A immunoadsorption for therapeutic purposes in cancer. The overall response rate, as reported in this study, is about 24%. About twothirds of the patients had no side effects, while others had flu-like symptoms, pain, and rash. Plasmapheresis, ordinarily a benign procedure, may cause serious side effects. These include 173-761 bleeding, citrate toxicity especially in patients with compromised liver functions, rash, urticaria, and occasionally hypotension and anaphylaxis. Patients with pre-existing electrolyte imbalance are at a greater risk of developing arrhythmias. If albumin or saline is used as a replacement fluid, laboratory coagulation parameters usually become abnormal but bleeding complications are rare [76]. Since almost all patients receive plasma infusions, they are also subject to the usual infectious side effects. There are 4 1 reported deaths associated with plasmapheresis [77]. There is little available data about the toxicity of plasmapheresis in cancer patients as such; but its risks, due to the generally poor nutritional status and at times presence of liver metastases, may be greater. In summary, plasmapheresis is a useful palliative therapy in patients with hyperviscosity syndromes due to multiple myeloma and Waldenstrom’s macroglobulinemia. Along with Protein A immunoadsorption, it may have a potential role in the management of TTP-like syndromes associated with malignancy and mitomycin C therapy. Partial and minimal antitumor responses have also been shown to Protein A immunoadsorption therapy. There is no evidence to support their use as a primary therapy in malignancy. Since plasmapheresis and Protein A immunoadsorption appear to alter immune reactivity in patients with cancer, these could be used as an investigative tool to better define the tumor-host relationship in this area.

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Therapeutic plasmapheresis and protein A immunoadsorption in malignancy: a brief review.

Plasmapheresis is being used with considerable frequency in the management of malignant and non-malignant disorders. More recently, staphylococcal Pro...
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