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Recombinant human erythropoietin (epoetin alfa) has been used in clinical settings for more than a decade. Its indications have expanded considerably from its original use as hormone therapy in the treatment of anemia in adults with chronic kidney disease. Since the introduction of epoetin alfa, a greater understanding of anemia pathophysiology and the interactions of erythropoietin, iron, and erythropoiesis has been elucidated. Anemia is now independently associated with increased mortality and disease progression. Potential survival benefits associated with correction of anemia in various patient populations are leading to consideration of earlier, more aggressive treatment of mild to moderate anemia with epoetin alfa. Moreover, this agent's therapeutic use may extend beyond currently accepted roles. Epoetin alfa is undergoing evaluation with promising results in a variety of new clinical settings, including anemia associated with congestive heart failure, ribavirin-interferon alfa treatment of hepatitis C virus infection, and critical illness. Preclinical studies also have established erythropoietin and its recombinant equivalent to be a pleiotropic cytokine with antiapoptotic activity and neuroprotective actions in the central nervous system. The therapeutic potential of epoetin alfa appears yet to be fully realized.

Hepatic hemosiderosis and increased iron absorption are common findings in cirrhosis. It has been proposed that a positive relation exists between intestinal iron absorption and the development of hepatic hemosiderosis. The current study investigated the duodenal expression of the iron transport molecules divalent metal transporter 1 (DMT1 [IRE]), iron-regulated gene 1 (Ireg1 [ferroportin]), hephaestin, and duodenal cytochrome b (Dyctb) in 46 patients with cirrhosis and 20 control subjects. Total RNA samples were extracted from duodenal biopsy samples and the expression of the iron transport genes was assessed by ribonuclease protection assays. Expression of DMT1 and Ireg1 was increased 1.5 to 3-fold in subjects with cirrhosis compared with iron-replete control subjects. The presence of cirrhosis per se and serum ferritin (SF) concentration were independent factors that influenced the expression of DMT1. However, only SF concentration was independently associated with Ireg1 expression. In cirrhosis, the expression of DMT1 and Ireg1 was not related to the severity of liver disease or cirrhosis type. There was no correlation between the duodenal expression of DMT1 and Ireg1 and the degree of hepatic siderosis. In conclusion, the presence of cirrhosis is an independent factor associated with increased expression of DMT1 but not Ireg1. The mechanism by which cirrhosis mediates this change in DMT1 expression has yet to be determined. Increased expression of DMT1 may play an important role in the pathogenesis of cirrhosis-associated hepatic iron overload.

Since its initial indication as hormone-replacement therapy in the anemia of chronic kidney disease, epoetin alfa has become a mainstay of therapy for chemotherapy-related anemia. Clinical studies have shown that epoetin alfa administered once weekly or three times weekly improves hemoglobin levels, decreases transfusion requirements, and improves quality of life independent of tumor response to chemotherapy. Ongoing research is now evaluating ways to improve the response rate to epoetin alfa, the potential benefits of alternative dosing regimens and early treatment intervention, and nonanemia-related indications (e.g., cognitive impairment, asthenia). In addition, scientists are exploring the role of epoetin alfa in preventing apoptosis and ischemic brain injury, as well as its activity in other nonerythroid tissues. Thus, the role of epoetin alfa is likely to expand in the cancer setting in the coming years.

Background: Previous reports have suggested that the use of recombinant human erythropoietin is effective for decreasing the need for perioperative allogeneic blood transfusion. The purpose of this study was to evaluate the efficacy of erythropoietin in combination with, and compared with, preoperative autologous donation for reducing allogeneic blood requirements for total joint arthroplasty., Methods: Two hundred and forty patients undergoing primary and revision total hip or knee arthroplasty were enrolled into three groups with different treatment regimens: (1) erythropoietin and preoperative autologous donation (Group 1), (2) erythropoietin alone (Group 2), and (3) preoperative autologous donation alone (Group 3). Patients were evaluated with regard to requirements for allogeneic transfusion, change from the baseline to the lowest postoperative hemoglobin value, postoperative complications, and adverse reactions., Results: The rate of allogeneic transfusion was 11% in Group 1 (erythropoietin and preoperative autologous donation) compared with 28% in Group 2 (erythropoietin alone) and 33% in Group 3 (preoperative autologous donation alone). Within Group 1, patients who had a unilateral primary arthroplasty had an allogeneic transfusion rate of 4% and those who had a bilateral or revision arthroplasty had an allogeneic transfusion rate of 17%. In Groups 2 and 3, the allogeneic transfusion rates were 14% and 15%, respectively, for the patients who had a unilateral primary arthroplasty and 35% and 47%, respectively, for those who had a bilateral or revision arthroplasty., Conclusions: Preoperative use of erythropoietin in conjunction with preoperative autologous donation reduces the need for allogeneic blood transfusion associated with total joint arthroplasty more effectively than does either erythropoietin or preoperative autologous donation alone.

Cancer-related anemia, in addition to having detrimental effects on quality of life and adding the risk and inconvenience of blood transfusions, may also be associated with decreased survival or time to progression. Yet despite increasing awareness of the value of treating cancer-related anemia, over 60% of US cancer patients receiving chemotherapy who have hemoglobin values below 10 g/dL are not treated for this condition. Current treatment options include red blood cell transfusions, iron supplementation for iron deficiency, or erythropoietic agents, including recombinant human erythropoietin (rHuEPO) and darbepoetin alfa (Aranesp). The articles in this supplement describe the basic scientific research and clinical development of darbepoetin alfa--another safe, effective, and approved treatment for chemotherapy-induced anemia.

This study was conducted to evaluate the validity and reliability of an instrument designed to measure risk of perineal skin injury in hospitalized individuals. Interrater reliability of the Perineal Assessment Tool was examined by correlating the scores calculated by a wound, ostomy and continence nurse compared to those calculated by staff RNs and LPNs using the same tool with the same patient. Content validity was assessed by obtaining level of agreement ratings from 102 wound, ostomy, and continence nurses. Good correlation between the expert and staff nurse scores was found (r = .970, confidence intervals = 95%, P = .923 to .988 or P < .0001). Average perineal assessment tool subscale level of agreement scores ranged from 7.66 to 8.4 (range 1 = strongly disagree to 10 = strongly agree) and the median score for all subscales was 9. The results obtained are encouraging and justify additional reliability and validity studies.

Background: Adenocarcinoma of the stomach and gastroesophageal junction results in substantial morbidity, locoregional recurrence, and death. Surgical procedures, even with adjuvant therapy, have not significantly improved survival. This study evaluated the toxicity, response rate, locoregional control, and survival of patients with locally advanced gastric cancer that was treated with neoadjuvant multimodality therapy., Methods: Patients with stage IIIA or early stage IV gastric adenocarcinoma received neoadjuvant 5-fluorouracil, Leucovorin, Adriamycin, and Cisplatin and underwent gastrectomy or esophagogastrectomy with intraoperative radiotherapy (IORT; 1000 cGY) to the gastric bed and postoperative radiation therapy., Results: Nine of 15 patients (60%) with transmural extension and/or nodal metastases received IORT. There were 2 pathologically complete responses at the primary site. Eleven of 15 patients (73%) had tumor in perigastric lymph nodes; however, 9 of 15 patients (60%) had mucin-filled nodes without tumor cells. Neoadjuvant treatment did not increase operative morbidity rates. Ten of 15 patients (67%) remain free of disease (median, 27 months; range, 6-60 months). Five patients died 13 to 41 months (median, 17 months) after diagnosis., Conclusions: Neoadjuvant multimodality therapy with neoadjuvant 5-fluorouracil, Leucovorin, Adriamycin, and Cisplatin, radical resection with IORT, and postoperative radiation therapy is safe, can downstage tumors, provides improved locoregional control, and appears to cause significant tumor regression that may result in long-term survival or cure.

Background: Central nervous system involvement is a common manifestation of non-Hodgkin lymphoma (NHL) in human immunodeficiency virus (HIV)-infected individuals. The purpose of this study was to review the frequency and pattern of neurologic manifestation of lymphoma in a cohort of HIV-infected individuals with systemic NHL., Methods: Sixty-two patients with HIV-associated systemic NHL received infusional cyclophosphamide, doxorubicin, and etoposide. Five patients with lymphomatous meningitis at presentation received whole brain radiation therapy plus intrathecal chemotherapy (ITC). Of the remaining 57 patients, prophylactic ITC was recommended only for those patients with lymphomatous bone marrow involvement and/or high grade histology (N = 31)., Results: Thirteen patients (21%) had histologically documented (N = 6) or presumed (N = 7) central nervous system involvement, including 7 patients (11%) with meningeal lymphoma discovered either at presentation (N = 5) or soon after diagnosis (N = 2), and 6 patients (10%) with cerebral mass lesions at the time of disease recurrence consistent with parenchymal brain involvement. Five of six parenchymal brain recurrences occurred in the setting of progressive systemic disease. Four of 7 patients (57%) with meningeal lymphoma detected at presentation (N = 5) or within 3 months of presentation (N = 2) responded to therapy and survived >1 year. Of the 26 patients assigned to receive no prophylactic ITC, no patient developed an isolated meningeal recurrence and 1 patient developed an isolated parenchymal brain recurrence., Conclusions: The findings of the current study suggest that in patients with HIV-associated systemic lymphoma, meningeal lymphoma is potentially curable, parenchymal brain recurrence usually occurs in the setting of uncontrolled systemic disease, and prophylactic ITC may not be necessary for patients with intermediate grade histology and uninvolved bone marrow., (Copyright 1999 American Cancer Society.)

Background: The factors contributing to blood transfusions in patients with anemia of chronic disease are not well documented in the literature. We analyzed all blood transfusion events within a single oncology practice to determine if certain chemotherapy drugs, cancer types, or other factors necessitated more frequent transfusions., Patients and Methods: Out of 331 patients receiving chemotherapy, 103 (31%) patients received a blood transfusion in 1995. Each of these charts was reviewed and sorted by diagnosis, treatment medications, and past transfusion and/or treatment history. Hemoglobin levels were obtained for each transfusion received in 1995., Results: The average hemoglobin at time of transfusion was 7.9 g/dl. Higher hemoglobin levels at transfusion were observed for patients over the age of 60 and patients who received prior chemotherapy. Lower hemoglobin levels at transfusion were observed for patients receiving Epoetin Alfa and sarcoma patients. The average number of red blood cell (RBC) units transfused in 1995 was 5.1 per patient. More units were given to patients receiving etoposide, while fewer units were given to those receiving ifosfamide. We created a transfusion severity index (TSI) to jointly measure these two variables., Conclusion: The results of this study identify transfusion needs associated with certain groups of cancer patients and with certain types of chemotherapy drugs.

Purpose: Kaposi's sarcoma (KS), the most common neoplasm in patients with AIDS, is a significant clinical problem for which current therapies are frequently unsatisfactory. We conducted a randomized phase III clinical trial to compare the efficacy and toxicities of a new form of therapy, pegylated-liposomal doxorubicin, with standard combination chemotherapy in patients with advanced AIDS-related KS (AIDS-KS)., Patients and Methods: Two hundred fifty-eight patients with advanced AIDS-KS were randomly assigned to receive either pegylated-liposomal doxorubicin (20 mg/m2) or the combination of doxorubicin (20 mg/m2), bleomycin (10 mg/m2) and vincristine (1 mg) (ABV) every 14 days for six cycles. Standard response criteria, toxicity criteria, and predefined indicators of clinical benefit were examined to evaluate outcomes., Results: Among 133 patients randomized to receive pegylated-liposomal doxorubicin, one achieved a complete clinical response and 60 achieved a partial response for an overall response rate of 45.9% (95% confidence interval [CI], 37% to 54%). Among 125 patients randomized to receive ABV, 31 achieved a partial response (24.8%; 95% confidence interval [CI], 17% to 32%). This difference was statistically significant (P < .001). In addition to objective responses, prospectively defined clinical benefits and toxicity outcomes also favored pegylated-liposomal doxorubicin., Conclusion: Pegylated-liposomal doxorubicin is more effective and less toxic than the standard combination chemotherapy regimen ABV for treatment of AIDS-KS.

High-dose chemotherapy (HDCT) with bone marrow transplantation (BMT) is associated with the development of significant anemia. The anemia is caused mainly by myelosuppression, although gastrointestinal-, genitourinary-, and phlebotomy-induced blood loss may also contribute. The number of red blood cell units transfused during the first 30 days following HDCT depends on the chemotherapy used, the underlying disease, and whether BMT was allogeneic, autologous, and used either peripheral blood stem cell or bone marrow support. Epoetin alfa has been used to treat the anemia that develops in the HDCT setting. Controlled studies in patients with both hematologic malignancies and solid tumors who were given epoetin alfa following HDCT have shown that red blood cell transfusion requirements decrease in patients receiving allogeneic BMT. Results using epoetin alfa in patients receiving autologous BMT have been disappointing. Alternatively, combination therapy with granulocyte colony-stimulating factor and epoetin alfa has been effective in mobilizing stem cell and committed myeloid/erythroid precursors before HDCT, but has not resulted in a lower red blood cell transfusion requirement after HDCT. Administration of epoetin alfa before HDCT while the bone marrow is still responsive to growth factors may be a new strategy with which to decrease the anemia in this setting.

Anemia is common in patients infected with the human immunodeficiency virus (HIV). The etiology is often multifactorial and may include the HIV infection itself, opportunistic infections, cancer, medications (particularly zidovudine and sulfa-containing drugs), or anemia of chronic disease. Epoetin alfa therapy may play a supportive role in some HIV-infected patients by increasing hemoglobin, decreasing fatigue, and reducing the need for exposure to red blood cell transfusions. A large, placebo-controlled trial in the United States for anemic patients with the acquired immunodeficiency syndrome taking zidovudine demonstrated a statistically significant improvement in hematocrit in patients treated with epoetin alfa compared with placebo. Transfusion requirements decreased in epoetin alfa-treated patients over a 3-month period compared with placebo with a trend toward improvement in quality of life. Epoetin alfa was effective, however, only in patients whose pretreatment erythropoietin levels were less than 500 mU/mL. These advantages of epoetin alfa treatment may become especially important as HIV becomes more of a chronic disease, with the concern that red blood cell transfusion may accelerate progression of HIV.

Protease inhibitors are an important new class of agents for the treatment of human immunodeficiency virus (HIV) infection. The purpose of our trial was to determine the feasibility of combining the protease inhibitor saquinavir with a 96-hour continuous intravenous infusion of cyclophosphamide (800 mg/M2), doxorubicin (50 mg/M2, and etoposide (240 mg/M2) (CDE) plus filgrastim in patients with non-Hodgkin's lymphoma associated with HIV infection. The effect of saquinavir on CDE-induced myelosuppression, CD4 lymphopenia, and non-hematologic toxicity was also sought. Twelve patients with HIV-related lymphoma received CDE every 28 or more days. All patients received saquinavir (600mg PO TID), filgrastim and Pneumocystis carinii and fungal prophylaxis. Patients also received either stavudine (n = 2) or both stavudine and didanosine (n = 10). Toxicity was analyzed using the NCI Common Toxicity Criteria for each cycle and the data were compared with the data from our prior study of CDE plus didanosine. An interim analysis was performed after accrual of the first 12 patients in order to assess toxicity. Severe (grade 3 or 4) mucositis occurred in eight of 12 patients (67%) treated with CDE plus saquinavir compared with three of 25 patients (12%) in our prior study treated with CDE without saquinavir (P < 0.001). In logistic regression analysis, saquinavir use was the only factor associated with a significantly greater risk of severe mucositis (relative risk 7.9; P = 0.03). Saquinavir use was not associated with a significant difference in the incidence of febrile neutropenia, prolonged neutropenia, chemotherapy dose reduction, or in the degree of myelosuppression. The decrease in CD4 lymphocytes for patients treated with saquinavir (absolute decrease of 23/microL, or a 26% decrease from baseline) was significantly less than for patients treated without saquinavir in the prior study (absolute decrease of 91/microL, or 42% decrease from baseline; P = 0.05). Four of 10 patients (40%) treated with saquinavir had an increase in CD4 lymphocytes of > or = 10/microL compared with none of 25 patients (0%) treated without saquinavir (P < 0.001). Combination of the protease inhibitor saquinavir with infusional CDE in patients with HIV-associated lymphoma was associated with a significant increase in the incidence of severe mucositis. This finding suggests that saquinavir may alter the metabolism of one of more of the cytotoxic agents in the CDE regimen, and underscores the need for careful investigation regarding the use of the protease inhibitors in patients receiving chemotherapy.

About 50% of cancer patients develop anemia; this incidence rises dramatically in patients with more advanced cancer or in those receiving chemotherapy or radiation therapy. Since the late 1980s, recombinant human erythropoietin (rHuEPO) has provided a safe and effective option for treating cancer-related anemia and fatigue. However, only about 50% of patients treated with rHuEPO adequately respond to therapy. In the chronic renal failure (CRF) population, true iron deficiency is the most common cause of an inadequate response to rHuEPO. Functional iron deficiency occurs when iron cannot be provided rapidly enough to meet the demands of rHuEPO-induced erythropoiesis, despite the presence of adequate bone marrow iron stores. It is hypothesized that functional iron deficiency can also occur in cancer patients receiving rHuEPO and may account for the lack of response in a proportion of the oncology population. Studies in CRF patients have shown that the administration of i.v. iron can correct functional iron deficiency more effectively than oral iron and may improve rHuEPO response. Therefore, it is important to monitor iron status and to address either true or functional iron deficiency prior to and during rHuEPO therapy to optimize the effect of rHuEPO in cancer patients. Studies are currently under way to determine the role of i.v. iron in treating cancer-related anemia.

Purpose: To determine the following: (1) the feasibility of combining the antiretroviral didanosine (ddl) with a 96-hour continuous intravenous (IV) infusion of cyclophosphamide (800 mg/m2), doxorubicin (50 mg/m2), and etoposide (240 mg/m2) (CDE) plus filgrastim in patients with non-Hodgkin's lymphoma (NHL) associated with human immunodeficiency virus (HIV) infection; (2) the effect of ddl on CDE-induced myelosuppression and CD4 lymphopenia; and (3) the effect of CDE on serum p24 antigen and quantitative HIV blood cultures., Methods: Twenty-five patients with HIV-related NHL received CDE every 28 or more days. Consecutive patients were assigned in an alternating fashion to group A (ddl given at a standard dose during cycles one, two, five, and six) or group B (ddl given during cycles three, four, five, and six)., Results: ddl use was associated with less leukopenia (mean nadir, 3.33 v 1.49 x 10(3)/microL; p = .03), neutropenia (2.38 v 1.07 x 10(3)/microL; p = .03), and thrombocytopenia (76 v 48 x 10(3)/microL; p = .059), and fewer RBC (1.6 v 3.1 per cycle; p < .01) and platelet transfusions (0.7 v 1.5 per cycle; p < .01), but had no significant effect on CD4 lymphopenia. Furthermore, lymphomatous bone marrow involvement and low CD4 count were associated with significantly greater myelosuppression. Although there was no substantial change in serum p24 antigen, the HIV blood culture became quantitatively more positive or converted from negative to positive in seven patients (64%). Complete response (CR) occurred in 58% of patients (95% confidence interval, 38% to 78%), median CR duration exceeded 18 months, tumor-related mortality was 20%, and median survival was 18.4 months., Conclusion: Our results suggest that the CDE and filgrastim regimen is tolerable and effective for patients with HIV-associated NHL, and that combination with ddl is feasible and may result in less myelosuppression.

Purpose: This article describes the mechanism of anemia in patients with cancer and the potential role of recombinant human erythropoietin in its treatment. Dosing, safety, prediction of response, and reimbursement issues also are discussed., Overview: Patients with advanced cancer frequently experience significant, chronic anemia that can contribute to overall morbidity. The causes of this anemia are multifactorial, including blood loss, nutritional deficiencies, hemolysis, bone marrow infiltration by tumors, and the anemia of chronic disease. In addition, myelosuppressive chemotherapy can cause or exacerbate this anemia., Clinical Implications: Several clinical studies have demonstrated that the use of recombinant human erythropoietin may prevent or ameliorate anemia by significantly increasing the hematocrit in patients who receive chemotherapy. This can reduce the proportion of patients who require erythrocyte transfusions. In addition, responding patients experience an improvement in quality of life.

Purpose: To assess whether the administration of recombinant human erythropoietin (r-HuEPO) would increase the hematocrit, reduce the requirement for transfusion, and improve the quality of life in anemic cancer patients receiving myelosuppressive, cisplatin-based chemotherapy., Patients and Methods: One hundred thirty-two anemic cancer patients receiving cyclic, cisplatin-containing, myelosuppressive chemotherapy were evaluated. Patients received either r-HuEPO (150 U/kg) or placebo, subcutaneously, three times a week for 3 months. Responses were assessed by measuring changes in hemoglobin/hematocrit, transfusion requirement, and quality of life., Results: The mean hematocrit increased by 6.0 percentage points in the r-HuEPO group versus 1.3 in the placebo group. A decrease in transfusion requirement did not reach significance over all 3 months, but there was a significant reduction in the percentage of patients transfused in the second and third months (27% r-HuEPO vs. 56% placebo) and a trend toward reduction in the mean total number of units transfused (1.20 units r-HuEPO vs. 2.02 units placebo), suggesting a lag of 1 month before r-HuEPO can affect the transfusion requirement. Pretreatment serum erythropoietin levels were lower in responders than in nonresponders (73.5 IU/L and 86.3 IU/L means, respectively). However, the magnitude of this difference was not helpful in defining which patients were likely to respond. There was a significant improvement in overall quality of life between the two treatment arms in favor of the r-HuEPO-treated group. There were no significant adverse effects associated with r-HuEPO., Conclusions: r-HuEPO is safe and can cause a significant improvement in the hematocrit and quality of life of anemic cancer patients receiving myelosuppressive, cisplatin-based chemotherapy. After 1 month of r-HuEPO, there is also a reduction in transfusion requirement.

Recombinant human erythropoietin has been available for clinical use since 1985. It was an immediate success in treating the anemia of chronic renal failure and has also enjoyed some objective success in the treatment of other anemias in either a therapeutic or prophylactic setting, but the issues of appropriate patient selection and cost-benefit ratios are still unresolved. This review discusses the most recent literature concerning the use of recombinant human erythropoietin for the anemia associated with cancer, HIV infection, myelodysplasia, prematurity, autologous blood transfusion, bone marrow transplantation, and chronic renal failure.

Anemia is common in patients with cancer and is often exacerbated by myelosuppressive chemotherapy. If severe enough, the anemia may require red blood cell transfusion for symptomatic palliation. However, blood transfusion will never be completely safe. Inconvenience and acute transfusion reactions are a problem and there is still a small risk of hepatitis. In selected patients with cancer-related anemia, recombinant human erythropoietin is another option to consider for the symptomatic patient.

Anemia is common in cancer patients and may require treatment for symptomatic palliation. Transfusion has been the mainstay of therapy, but is not without risk. Because erythropoietin levels in cancer-related anemia are inadequate for the degree of anemia, recombinant human erythropoietin has been studied to treat the anemia. Results from these studies are encouraging.

To evaluate the effect of recombinant human erythropoietin on anemia and health-related quality of life in patients with acquired immunodeficiency syndrome (AIDS), we initiated an observational study with an open-label multicenter treatment protocol that involved multiple academic and community physicians in the United States. Our subjects comprised 251 anemic (i.e., hematocrit < 30%) patients with a clinical diagnosis of AIDS using 1987 CDC criteria, age > or = 12 years, and serum erythropoietin level < or = 500 IU/L. The initial dosage of recombinant human erythropoietin was 4,000 units subcutaneously for 6 days each week. Based on the patient's response to therapy, the dosage was increased sequentially to 8,000 units subcutaneously for 6 days per week. Our measurements included changes in mean hematocrit and health-related quality of life. The interview included measures of energy/fatigue; physical, social, role and cognitive function; depression; health perceptions; and life satisfaction. Adverse experiences were also documented to assess safety. Changes in mean hematocrit level from a baseline of 27.9% to 33.6% at week 12 (p < .0001) and 34.5% at week 24 (p < .0001) were observed in patients treated with recombinant human erythropoietin. Adverse experiences, not clearly associated with AIDS, were reported by 10% of patients. Increases in energy (p < .05) were observed after 12 and 24 weeks of drug therapy, and increases in health perceptions were seen after 24 weeks (p < .05). No statistically significant increases or decreases were observed on measures of physical functioning, cognitive functioning, depression, social functioning, or home management activities over the 24-week follow-up. Anemia correctors (defined as hematocrit > or = 38%) showed greater improvement in energy, health perceptions, home management, and role function than noncorrectors. Study dropouts and those who died had significantly worse scores for health-related quality of life at baseline compared to study completers. Thus, the AIDS patients with anemia and serum erythropoietin levels < or = 500 IU/L treated with recombinant human erythropoietin showed increased mean hematocrit and improved health perceptions and energy levels. The drug therapy was associated with increased feelings of energy, but it was not associated with other changes in health status and well-being in the AIDS patients completing the study. These observations need to be confirmed in randomized clinical trials.

Anemia associated with advanced cancer is common. Contributing factors include the anemia of chronic disease, chemotherapy, radiation therapy, and bone marrow invasion with tumor. Based on the observation that endogenous erythropoietin (EPO) levels in anemic patients with cancer are inadequate for the degree of anemia, three randomized double-blind, placebo-controlled trials of recombinant human erythropoietin (rHuEPO) treatment in anemic patients with cancer were performed in patients (1) not receiving concomitant chemotherapy (NO CTX), (2) receiving myelosuppressive chemotherapy that did not include cisplatin (CTX-NO PLAT), and (3) receiving myelosuppressive cisplatin-containing chemotherapy (CTX-PLAT). In the NO CTX trial, patients were treated with rHuEPO 100 U/kg or placebo subcutaneously (SQ) three times per week for up to 8 weeks. In the CTX trials, patients were treated with rHuEPO 150 U/kg or placebo SQ three times per week for 12 weeks. Four hundred thirteen patients were enrolled (124, NO CTX; 157, CTX-NO PLAT; and 132, CTX-PLAT). In all three trials, patients receiving rHuEPO had a significantly (P < .004) greater increase in hematocrit (HCT) than placebo-treated patients. In the two CTX trials combined, rHuEPO-treated patients also had a significantly (P < or = .009) lower transfusion requirement than placebo-treated patients after the first month of therapy. Quality of life improved significantly (P < .05) in responding (> or = 6%-point HCT increase without transfusion) rHuEPO-treated patients compared with placebo-treated patients. Overall, no adverse events occurred more frequently in rHuEPO-treated patients compared with placebo-treated patients. Following completion of the double-blind phase, patients received rHuEPO on an open-label basis as needed for correction of anemia with the dose titrated to a maximum of 900 U/kg/wk. During total rHuEPO exposure (either started at the beginning of double-blind therapy for patients initially randomized to rHuEPO or at the beginning of open-label therapy for patients initially randomized to placebo; 363 treated/347 evaluable for efficacy), 40.0%, 56.1%, and 58.3% of the NO-CTX, CTX-NO PLAT, and CTX-PLAT patients, respectively, responded to rHuEPO therapy with an increase of HCT > or = 6% unrelated to transfusion.(ABSTRACT TRUNCATED AT 400 WORDS)

The results of the multicenter trials demonstrate that r-HuEPO therapy can increase the hematocrits of anemic patients with advanced cancer. The multicenter trials were undertaken because, in previous smaller trials without placebo controls, patients with cancer and anemia had been shown to be likely responders to r-HuEPO therapy. To varying degrees in these trials, RBC transfusion requirements were eliminated or decreased in comparison to those of placebo-treated patients, and anemia was lessened or corrected in the r-HuEPO groups. The side effects of r-HuEPO treatment were minor; anemic patients with advanced cancer receiving r-HuEPO therapy did not develop significant hypertension, seizures, or thrombotic events, and progression of tumor was not observed. Moreover, patients in the multicenter trials whose hematocrits increased to 38% or greater, or increased 6 percentage points or more, experienced significant improvement in all aspects of the quality of their lives. On the basis of these trials, r-HuEPO therapy appears to treat effectively the anemia of cancer. The importance of eliminating the need for transfusions and preventing sensitization to human leukocyte antigens will be major factors affecting the clinical future of r-HuEPO.

Background: Patients with advanced cancer frequently experience clinically significant anemia, which is often exacerbated by myelosuppressive chemotherapy. Consistent with the anemia of chronic disease, studies have documented serum erythropoietin levels that are inappropriately low for the degree of anemia in cancer patients. Myelosuppressive chemotherapy impairs erythropoiesis, which may not fully recover between treatment cycles. Recombinant human erythropoietin (rHuEPO) has been used safely and effectively to treat anemia in AIDS patients receiving zidovudine (AZT) and in patients with chronic renal failure., Purpose: This study was designed to evaluate the clinical role of rHuEPO in reducing symptomatic anemia in patients with advanced cancer who were receiving myelosuppressive chemotherapy (excluding cisplatin)., Methods: We studied 153 anemic cancer patients receiving cyclic combination chemotherapy in a prospective multicenter, double-blind, placebo-controlled trial. The patients were randomly assigned to receive either rHuEPO (150 U/kg) or placebo subcutaneously three times a week for a maximum of 12 weeks or until the hematocrit level increased to 38%-40%. If the hematocrit reached this target level before 12 weeks, the rHuEPO dose could be reduced to maintain the hematocrit at that level for the duration of the study. Response to rHuEPO therapy was assessed by measuring changes in hematocrit level, transfusion requirements, and quality of life. Quality-of-life assessment was based on patients' responses to questionnaires before and after the courses of therapy., Results: The increase in hematocrit in the rHuEPO-treated group compared with hematocrit in the placebo-treated group was statistically significant (P = .0001) as measured by percentage point of change from baseline to final evaluation, by an increase in hematocrit level of six percentage points or more unrelated to transfusion, and by a rise in hematocrit level to 38% or more unrelated to transfusion. There was a trend toward the reduction in mean units of blood transfused per patient during months 2 and 3 of therapy combined in rHuEPO-treated patients compared with placebo-treated patients (0.91 U versus 1.65 U; P = .056). In addition, rHuEPO-treated patients experienced a statistically significant improvement in energy level and ability to perform daily activities (P < or = .05). The two treatment groups showed no statistically significant differences in toxic effects except for increased incidence of diaphoresis (P < .05) and diarrhea (P = .05) in the rHuEPO-treated group., Conclusions: We conclude that rHuEPO is safe and effective for reversing anemia related to advanced cancer or to chemotherapy for cancer.

Objective: To evaluate the safety and efficacy of zalcitabine (also known as dideoxycytidine [ddC]) in patients with advanced human immunodeficiency virus (HIV) infection., Design: Open-label, randomized study., Setting: AIDS Clinical Trials Units, university-affiliated medical centers, and private practice groups., Patients: Patients with the acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex who had tolerated zidovudine for 48 weeks or more., Intervention: Fifty-nine patients received zidovudine (500 to 1200 mg/d) and 52 patients received zalcitabine (2.25 mg/d)., Measurements: The primary end points were survival and time to an AIDS-defining event or death., Results: Because significantly more patients withdrew from zidovudine therapy, the median duration of treatment was greater in the zalcitabine group than in the zidovudine group (279.0 days compared with 174.5 days; P = 0.001). The estimated 12-month, event-free probabilities were 53% for the zalcitabine group and 57% for the zidovudine group (relative risk, 1.02; 95% CI, 0.5 to 2.2). The estimated 12-month survival rates were 81% for the zalcitabine group and 75% for the zidovudine group (relative risk, 1.39; CI, 0.5 to 3.8). The rate of decline in CD4 lymphocyte counts was significantly slower in the zalcitabine group than in the zidovudine group (-0.08 cells/day compared with -0.17 cells/day). Patients in the zalcitabine group had gained an average of 0.5 kg at week 20 and 0.4 kg at week 24, whereas patients in the zidovudine group had lost an average of 1.8 kg at week 20 and 2.4 kg at week 24 (P = 0.04 and P = 0.05, respectively). Moderate to severe peripheral neuropathy and ulcerative stomatitis occurred in 10 and 9 patients, respectively, in the zalcitabine group., Conclusions: The sample size for this study was smaller than planned, and no differences in survival and clinical end points were found. Slower rates of decline in CD4 lymphocyte counts and weight, however, were noted for the zalcitabine group.

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.

Objective: To assess the effect of recombinant human erythropoietin (r-HuEPO) on anemia in patients with the acquired immunodeficiency syndrome (AIDS) who are receiving zidovudine therapy., Design: Combined analysis of four 12-week, randomized, double-blind, controlled clinical trials., Setting: Multiple centers in the United States., Patients: Two hundred and ninety-seven anemic (hematocrit < 30%) patients with AIDS who were receiving zidovudine therapy. Of the 297 patients, 255 were evaluable for efficacy, but all patients were included in analysis of safety., Intervention: Patients were randomly assigned to receive either r-HuEPO (100 to 200 U/kg body weight) or placebo, intravenously or subcutaneously, three times per week for up to 12 weeks., Measurements: Changes in mean hematocrit, transfusion requirement, and quality of life., Results: Sixty-nine percent of patients had endogenous serum erythropoietin levels less than or equal to 500 IU/L, and 31% had erythropoietin levels greater than 500 IU/L. In patients with low erythropoietin levels (< or equal to 500 IU/l), r-HuEPO therapy decreased the mean number of units of blood transfused per patient when compared with placebo (3.2 units and 5.3 units, respectively; P = 0.003) and increased the mean hematocrit from the baseline level (4.6 percentage points and 0.5 percentage points, respectively; P <0.001). Overall quality of life improved in patients on r-HuEPO therapy (P = 0.13). Patients with erythropoietin levels greater than 500 IU/L showed no benefit from r-HuEPO in any outcome variable. Placebo and r-HuEPO recipients did not differ in the incidence of adverse effects or opportunistic infections., Conclusion: Therapy with r-HuEPO can increase the mean hematocrit and decrease the mean transfusion requirement in anemic patients with AIDS who are receiving zidovudine and have endogenous low erythropoietin levels (< or equal to 500 IU/L). Such therapy is of no apparent benefit in patients whose endogenous erythropoietin levels are higher than 500 IU/L.

There exists a potential for change in the approach to the management of the patient with chronic disease, specifically, the anemia of chronic disease (ACD). One of the components in the pathophysiology of ACD is inadequate erythropoietin response. Normally, as anemia develops, the erythropoietin level does not begin to increase until the hematocrit level decreases below 35%. However, the increase in the erythropoietin level is blunted in ACD. Increasing the hematocrit level by transfusion or recombinant human erythropoietin (r-HuEPO) treatment can subjectively and objectively improve the ACD patient's symptoms and performance. Although objective data in support of blood transfusions do exist, this treatment can carry risks of acute and chronic reactions, infection, and possibly immunosuppression. Treatment with r-HuEPO is a safer, nontransfusion means of increasing the hematocrit level of the patient with ACD symptoms.

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.

Objective: To determine if a 6-month course of therapy with IMREG-1, a leukocyte-derived immunomodulator, slows disease progression in patients with AIDS-related complex., Design: Randomized, double-blind trial., Setting: Five academic- and three community-based clinics., Patients: Immunocompromised patients (143) with HIV., Interventions: IMREG-1 or placebo every 2 weeks (13 doses)., Main Results: Twelve of forty-eight patients on placebo and 5 of 95 patients on IMREG-1 experienced adverse events (AIDS-defining opportunistic infection or neoplasm, wasting syndrome, HIV-associated encephalopathy, or peripheral sensory neuropathy). Based on an intention-to-treat analysis, Kaplan-Meier event probabilities were 26% for the placebo group and 6% for the IMREG-1 group (P less than 0.001); based on the Cox proportional hazards model, the relative risk for patients on placebo compared with patients on IMREG-1 was 5.1 (95% CI, 1.8 to 14.8). The frequency of symptoms significantly increased from baseline in patients receiving placebo. The mean decrease in CD4+ cells from baseline was 80 x 10(6) cells/L in the placebo group and 29 x 10(6) cells/L in patients on IMREG-1, with 20% (8) and 38% (32) of patients, respectively, showing a trend toward an increase (P = 0.04). In patients receiving IMREG-1, the size and rate of delayed hypersensitivity responses were larger than in the placebo group., Conclusions: Patients with AIDS-related complex experienced fewer adverse events and constitutional symptoms after IMREG-1 treatment. The slower loss of CD4+ cells and increased size and rate of delayed hypersensitivity responses most likely reflect the effect of IMREG-1 on the immune system. No toxicity related to IMREG-1 administration was observed.

Extracorporeal removal or modulation of circulating immune complexes (CIC) from plasma of animals and humans with malignant disease may be associated with induction of immune-mediated anti-tumor responses. Immunoadsorption columns containing heat-killed and formalin-fixed Staphylococcus aureus or staphylococcal protein A have been used for this purpose but treatments have often been associated with cardiopulmonary toxicity. Recently, an immunoadsorption device containing highly purified protein A covalently attached to a silica matrix (PROSORBA column) was used to treat 142 patients with refractory malignancies and 22 of 104 patients evaluated for anti-tumor response had objectively measurable reduction in tumor burden. In contrast to earlier experience with other devices, the procedures used in this trial were well tolerated and could be performed on an outpatient basis. The most common side effects observed among 1,306 treatments were chills (28% of treatments), low grade fever (28%), and musculoskeletal pain (16%). Side effects were mild to moderate and required no treatment or only symptomatic treatment. Treatment schedules were interrupted due to side effects for only six patients and there were no treatment-related deaths. Of 64 patients available for long-term follow-up evaluation (mean of 11 months), none exhibited evidence of long-term treatment-related side effects. None of the patient deaths in that period were associated with short or long-term treatment-related side effects. Protein A-silica (PROSORBA columns) can be used safely for development of further experimental treatments of malignant disease.

Bone marrow suppression and anemia are frequent side effects of treatment of the acquired immunodeficiency syndrome (AIDS) with zidovudine (formerly azidothymidine [AZT]). We conducted a randomized, double-blind, placebo-controlled clinical trial of recombinant human erythropoietin (100 U per kilogram of body weight thrice weekly by intravenous bolus) in 63 patients with AIDS treated with zidovudine (29 in the erythropoietin group and 34 in the placebo group). Reductions in the number of units of red cells transfused and the number of patients given transfusions per month became apparent in the second and third months of the trial. The reductions were observed in patients with endogenous erythropoietin levels less than or equal to 500 IU per liter at base line, but not in patients whose levels were greater than 500 IU per liter at the beginning of the study. Although the hematocrit and hemoglobin level were not used as the primary criteria of efficacy because the patients received transfusions when their physicians decided that they needed them, a significantly higher rate of increase in the hematocrit was observed in the patients treated with recombinant human erythropoietin whose levels of endogenous erythropoietin were less than or equal to 500 IU per liter (0.00353 points per week) than in the patients given placebo (0.00116 points per week). This effect was not seen in patients with higher levels of endogenous erythropoietin. Serious side effects did not occur more often in the group treated with erythropoietin than in the placebo group. We conclude that recombinant human erythropoietin may be useful in patients with AIDS treated with zidovudine, although the indicators for its use remain to be clarified.

The effect of plasma exchange on the pharmacokinetics of prednisone and prednisolone was studied. Two patients undergoing plasma exchange while receiving oral prednisone therapy were studied. Patient 1 received prednisone 50 mg daily; patient 2 received 60 mg daily. On a day when the patients were to undergo plasma exchange, blood samples for determination of prednisone and prednisolone concentrations were obtained just before the daily prednisone dose and at various times before, during, and after plasma exchange. The amount of both drugs in plasma removed by plasma exchange was also determined. On a day when the patients were not receiving plasma exchange therapy, additional blood samples were obtained just before the daily prednisone dose and at 0.5, 1, 2, 4, 6, and 8 hours after the dose. Values for elimination rate constant, half-life, area under the curve, clearance, and volume of distribution on and off plasma exchange were calculated from serum concentration-time curves for prednisone and prednisolone. Only prednisolone data proved adequate for pharmacokinetic calculations. Values of pharmacokinetic variables for prednisolone on and off plasma exchange did not differ substantially in either patient. The amount of combined prednisone and prednisolone removed by plasma exchange in each patient was less than 1% of the administered prednisone dose. In the two patients studied, changes in pharmacokinetic values for prednisolone attributable to plasma exchange and the amount of combined prednisone and prednisolone removed by plasma exchange were minimal. Supplemental dosing of prednisone following plasma exchange appears unnecessary.

Thrombocytopenia is a well-described complication of heparin therapy. Few studies describe the incidence of thrombocytopenia when low-dose heparin (10,000-15,000 units/day) is used for prophylaxis of deep venous thrombosis. In our study, ten of 66 courses (15%) of heparin prophylaxis in coronary care unit patients were accompanied by a mild thrombocytopenia with platelet counts below 150 X 10(3)/mm3. In all cases the platelet count returned to normal despite continued heparin therapy. Patients who became thrombocytopenic had significantly lower initial platelet counts. No cases of severe thrombocytopenia were seen (platelet count below 100 X 10(3)/mm3). No patient developed thrombosis, bleeding or elevated fibrin split products. Mild thrombocytopenia occurring after 2-5 days of low-dose heparin is common, but clinically insignificant.

Circulating immune complexes (CIC) are known to be present in cancer patients and are responsible for much of the cancer-associated immunosuppression. Removal or modulation of these "blocking factors" can reverse the immunosuppression. Protein A from Staphylococcus aureus has the unusual property of binding to CIC with high avidity. Use of protein A as an immunoadsorbent in extracorporeal immunotherapy affinity columns has resulted in antitumor and antiviral responses in animals. Our group developed a multicenter trial to assess toxicity and antitumor response with this biologic response modifier alone. Overall, 24% (21 of 87 patients) had objective tumor regressions including both partial responses (PR) and less than PR. No complete responses (CR) were observed. Responses were observed in acquired immune deficiency syndrome (AIDS)-related Kaposi's sarcoma (six of 17 PR; two of 17 less than PR; overall, 47%), breast adenocarcinoma (five of 22 PR; three of 22 less than PR; overall response, 36%), colon adenocarcinoma, (one PR, one less than PR; overall response, 11%), and non-oat cell lung carcinoma (two of seven less than PR). The procedure was well tolerated and could be performed on an outpatient basis. No adverse reaction was observed in 735 of 1,113 treatments (66%). The most common adverse effect was an "influenza-like" syndrome consisting of fever and chills. Pain was present in 12% of the patients. There were no study-related deaths. Serum IgG and CIC levels did not statistically change due to therapy in responding or nonresponding patients. Complement levels remained within the normal range. Liver and renal tests remained stable throughout the study. In summary, protein A immunoadsorption of plasma is well tolerated in the outpatient clinic, has demonstrated antitumor activity in resistant solid tumors, and functions as a biologic response modifier.

Protein A, a naturally occurring Staphylococcus aureus cell surface protein, has the unusual property of binding circulating immune complexes and immunoglobulin G with high avidity. CIC have played a major role in cancer-associated immunosuppression. Thus, removal of the immunosuppressive agents, ie, the CIC, may lead to a modulation of the immunosuppression and a liberation of the immune system to perform an antitumor effect. In animal studies, protein A has been used in extracorporeal immunoadsorption columns and treatments have resulted in tumor shrinkage and antiviral responses. Our group developed a multicenter clinical trial to assess toxicity and antitumor responses with this biologic response modifier alone. This is an update of our original trial. We have now treated 142 patients for a total of 1,306 treatments. The patients consisted of 74 males and 68 females. Their age ranged from 7 to 83 years, with a mean of 50 years. The Karnofsky performance index values ranged from 40 to 95, with a mean of 80. Patients who received seven or more treatments were considered eligible for tumor response assessment, and all patients with one or more treatments were eligible for toxicity assessment. Thus, there were 101 patients eligible for tumor response and 142 eligible for toxicity response. The total response rate was 22 patients or 21.8% (partial remission [PR], 12 patients, 12%; less than PR, 10 patients, 10%). Response rates were similar in the 13 treatment centers. Toxicity was assessed in 142 patients. One thousand three hundred six treatments were assessed for treatment toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Perfusion of plasma from tumor-bearing animals over Staphylococcus aureus with membrane-bound protein A has resulted in significant tumor shrinkage. Similar therapy has now been given to 16 patients by three methods. No tumor responses have been observed. Five patients were treated with perfusion over fixed and killed S. aureus Cowan I. Cardiovascular and respiratory toxicity was excessive and appeared to be related to volume and rate of plasma infused. Eight patients were treated with perfusion of autologous plasmas over protein A-collodion-charcoal. Doses of plasma ranged from 50 to 450 ml. No toxicity was noted. Three patients have been treated with perfusion over protein A-silica. Toxicity in two resembled that seen in the S. aureus trials, although it was not as severe. We conclude that the toxicity of this therapy can be life-threatening, and human trials should be undertaken with caution.

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.

Both antibodies and circulating immune complexes (CIC), which bind to platelets and induce the destruction and clearance of platelets by the reticuloendothelial system, are found in patients with human immunodeficiency virus (HIV) and immune thrombocytopenic purpura (ITP). IgG and CIC were removed from patients' plasma by extracorporeal immunoadsorption using protein A-silica columns (PROSORBA columns). Of the 36 HIV-positive ITP patients treated, 29 received more than one treatment and were evaluated for response. Sixteen patients showed more than a 50% increase in their platelet counts. Platelet-associated IgG (PAIgG) and/or platelet-directed IgG and CIC were elevated in all patients. After four to eight treatments, 16 of 29 patients showed a 170% to 430% increase in platelet counts. A decrease in CIC and PAIgG was noted in responding patients. The median duration of response to date was 8 to 12 months. This treatment was associated with immune modulation and the development of an anti-F (ab')2 antibody response. The antibody functions by complexing with both platelet-binding IgG and CIC, neutralizing their binding capacity for platelets and enhancing their clearance from the circulation. Nine patients with mitomycin-C-induced hemolytic uremic syndrome (HUS) were also treated with PROSORBA columns. Pretreatment platelet counts were markedly reduced while a definite increase in platelet counts was observed upon completion of therapy. There was a decrease of hemolysis and stabilization of renal function in three patients. PROSORBA column treatment has demonstrated marked activity against both HIV-ITP and HUS, and has successfully freed patients from the bleeding diathesis associated with these syndromes.