Included Injection Site Reactions Research Articles

Imiquimod: A TLR-7 agonist as adjuvant for a recombinant protein cancer vaccine

8545 Purpose: This clinical trial evaluates the safety and adjuvant activity of imiquimod, a toll-like receptor (TLR)-7 agonist, when given with a NY-ESO-1 protein vaccine. Imiquimod, by locally activating and recruiting dendritic cells (DCs) into the skin, is expected to stimulate antigen uptake by DCs, induce maturation and migration to draining lymph nodes, and to induce antigen-specific T and B cell immunity. Methods: Pilot study; 9 patients with resected stage 2B-3C malignant melanoma. Four 21 day cycles consisted of topical imiquimod cream (250 mg) on days 1–5 and id. injected NY-ESO-1 protein (100 mcg) into the site on day 3. Blood was drawn at several time points for immune monitoring; skin punch biopsies were obtained from control, imiquimod and vaccination sites 48 hours after the last vaccination. Results: The regimen was tolerated well, all patients completed four vaccinations. AEs were mild and transient and included injection site reactions (8/9 patients), fatigue (4/9 patients) and fever (2/9 patients). Significant levels of antigen-specific CD4+ or CD8+ T cell responses were not detected in ex-vivo ELISPOT assays. However, intracellular cytokine staining assays after in vitro pre-stimulation indicated that 6 of 8 subjects developed NY-ESO-1 CD4+ T cell responses. Humoral immunity was manifest by the induction of anti-NY-ESO-1 antibodies in 7/9 patients post-vaccination. Histochemistry of skin sections showed significant dermal mononuclear cell infiltrates in Imiquimod treated skin, whereas none were seen in untreated skin (p<0.01). IHC revealed markedly increased numbers of CD3+ (T-cells), CD68+ (macrophages/monocytes), CD123+ (plasmacytoid DCs) and DC-LAMP+ (mature myeloid DCs) immune cells in Imiquimod treated skin when compared with control skin of the same patients (p<0.05). Conclusion: Imiquimod, a topical immune response modifier, generated clear inflammatory infiltrates in the dermis, with significant increases in antigen-presenting cells and T cells. Imiquimod was well tolerated when used as an adjuvant to an NY-ESO-1 protein vaccine. Systemic immunity of both humoral and cellular types was induced in the majority of patients; however, responses were weak and the vaccine combination needs to be optimized in future studies. No significant financial relationships to disclose.

Clinical Pharmacodynamic Effects of the Growth Hormone Receptor Antagonist Pegvisomant: Implications for Cancer Therapy

The present study evaluated and compared the efficacy of pegvisomant and octreotide in blocking the growth hormone (GH) axis in humans based on pharmacodynamic biomarkers associated with the GH axis. The study also evaluated the safety of pegvisomant given at high s.c. doses for 14 days. Eighty healthy subjects were enrolled in five cohorts: cohorts 1 to 3, s.c. pegvisomant at 40, 60, or 80 mg once dailyx14 days (n=18 per cohort); cohort 4, s.c. octreotide at 200 microg thrice dailyx14 days (n=18); and cohort 5, untreated control (n=8). Serial blood samples were collected to measure plasma concentrations of total insulin-like growth factor type I (IGF-I), free IGF-I, IGF-II, IGF-binding protein 3 (IGFBP-3), and GH in all subjects and serum pegvisomant concentrations in subjects of cohorts 1 to 3. All subjects receiving treatment were monitored for adverse events (AE). After s.c. dosing of pegvisomant once daily for 14 days, the mean maximum suppression values of total IGF-I were 57%, 60%, and 62%, at 40, 60, and 80 mg dose levels, respectively. The maximum suppression was achieved approximately 7 days after the last dose and was sustained for approximately 21 days. Pegvisomant also led to a sustained reduction in free IGF-I, IGFBP-3, and IGF-II concentrations by up to 33%, 46%, and 35%, respectively, and an increase in GH levels. In comparison, octreotide resulted in a considerably weaker inhibition of total IGF-I and IGFBP-3 for a much shorter duration, and no inhibition of IGF-II. AEs in pegvisomant-treated subjects were generally either grade 1 or 2. The most frequent treatment-related AEs included injection site reactions, headache, and fatigue. Pegvisomant at well-tolerated s.c. doses was considerably more efficacious than octreotide in suppressing the GH axis, resulting in substantial and sustained inhibition of circulating IGF-I, IGF-II, and IGFBP-3 concentrations. These results provide evidence in favor of further testing the hypothesis that pegvisomant, through blocking the GH receptor-mediated signal transduction pathways, could be effective in treating tumors that may be GH, IGF-I, and/or IGF-II dependent, such as breast and colorectal cancer.

Phase II trial of GM-CSF in women with asymptomatic müllerian cancer

5081 Background: GM-CSF is a recombinant human cytokine, which increases the proliferation of granulocytes and monocytes. Experience with this agent, including adjuvant studies in melanoma, vaccine-based studies using autologous tumor vaccines that secrete human GM-CSF, and studies in prostate cancer using GM-CSF have all suggested that GM-CSF might provide anti-tumor activity in a subset of cancer patients. Methods: Open label phase II study performed in asymptomatic patients with recurrent mullerian malignancy without an indication for immediate systemic chemotherapy. Patients could have measurable or evaluable disease (defined as CA-125 >35 U/ml or 2 successively rising values with the most recent 3x the nadir value.) GM-CSF 250 mcg/m2 was administered subcutaneously on days 1–14 of a 28-day cycle. Monthly follow-up included interim history, physical exam and CA-125, with radiologic evaluation q 3 months. Results: Enrollment to this cohort is complete. Thirty-five women with a median age of 60 were enrolled; data are available on 33:30 women with ovarian and 3 with primary peritoneal cancers. To date 31 women are evaluable for response. Best overall response of patients who have completed the study includes 6 patients with stable disease (18%). Median time to treatment termination (TTT) was 76 days. Four patients remain on study, 2 with SD >6 months. Toxicity was generally mild, including injection site reaction, fatigue, and bone pain, however 2 patients experienced excessive toxicity and withdrew consent. There were 3 bowel obstructions thought related to disease but contribution of drug could not be ruled out. After 14 days of GM-CSF, CA-125 dropped in 23 of 33 women (70%) from their baseline on study value (median change -23%, range −48 to +158%). The magnitude of CA-125 drop during the first two weeks of therapy was significantly and positively correlated with day 15 WBC (p = 0.04.) Conclusions: GM-CSF is well tolerated and frequently associated with a decline in CA-125 that is correlated with leukocytosis. Although median TTT for the entire group is modest, a subset of women have had prolonged stable disease. Strategies to maintain and titrate leukocytosis are now being explored in a separate cohort. No significant financial relationships to disclose.

In Smoldering/Indolent (SMM/IMM) Myeloma Patients Treated with Interleukin-1 Receptor Antagonist (IL-1Ra), Responders Demonstrate a Significantly Increased Time to Progression (TTP) and a Decreased C-Reactive Protein (CRP) Compared with Nonresponders.

Background: Patients with SMM/IMM are at high risk for progression to active MM and are appropriate candidates for chemoprevention trials. High IL-1beta levels are a useful surrogate marker for progression from SMM/IMM to active myeloma.Methods: We carried out a Phase II clinical trial of IL-1Ra (Anakinra) in patients with SMM/IMM to determine the biologic activity, progression-free rate, and toxicity of IL-1Ra. Since IL-1beta induces paracrine IL-6, we hypothesized that IL-1Ra would inhibit IL-6 production and myeloma cell growth. Patients that had ≥ 10% bone marrow plasma cells and/or an IgG or IgA M-spike ≥ 3 g/dL and did not require immediate chemotherapy were eligible. Patients received 100 mg of Anakinra (IL-1Ra) SQ qd for a total duration of 6 months. Non-progressors were allowed to continue on therapy with IL-1Ra until they converted to active myeloma. IL-1beta levels were measured in a bioassay with a read out of IL-1 inducible IL-6 production. CRP levels served as a surrogate for IL-6 production.Results: Thirty-six patients are included for analysis based on intent to treat at diagnosis. At baseline, twenty-nine patients had elevated functional IL-1beta levels consistent with progressive disease and 12 patients had radiologic evidence of disease on bone survey. The median TTP for the entire group was 1 year and 2 patients exhibited a minor response based on M-protein reduction. A proportional hazards analysis was performed and the variables examined were: % bone marrow plasma cells, plasma cell labeling index (PCLI), circulating plasma cells, albumin, M-protein level, IgA subtype, CRP, CRP % reduction ≥ one-third, beta-2 microglobulin, creatinine, calcium, hemoglobin, urine total protein, presence of lytic bone disease, and IL-1 level. Univariate Cox model results showed that % BMPC, PCLI, circulating plasma cells, CRP % reduction, presence of lytic disease, and IL-1 level were all statistically significant (p < .05) variables. However, only the CRP % reduction from baseline remained significant in the multivariate analysis (p < 0.01). The median TTP for patients without (n=18) and with (n=18) a decrease in CRP was 6 months and > 2 years, respectively (p < .0001). Toxicities included injection site reactions during the first month of therapy and asymptomatic neutropenia necessitating a reduction in therapy to every other day. Five patients in whom the CRP decreased and the baseline PCLI was > 0 also demonstrated a parallel decrease in the PCLI. Several of the patients with progressive disease on IL-1Ra alone could later be rescued with the addition of low dose dexamethasone (20 mg once a week) suggesting that the endogenous IL-1beta levels were too high to inhibit with IL-1Ra alone. Conclusion: In summary, IL-1Ra can prolong the TTP to active myeloma in responsive SMM/IMM patients through inhibition of IL-6 production (decrease in CRP) and myeloma cell growth. [Display omitted]

Phase I trial of escalating doses of the TLR9 agonist HYB2055 in patients with advanced solid tumors

2503 Background: HYB2055 (IMOxine) is a novel agonist of Toll-like receptor 9 (TLR9) and shows potent antitumor activity in mouse models. HYB2055 was well tolerated in a phase I multiple-dose volunteer trial. Methods: IMOxine was administered to 23 refractory cancer patients with advanced solid tumors by weekly subcutaneous injection. Treatment continued on a 4-w cycle based on tolerance and absence of disease progression as assessed by RECIST. Dose limiting toxicity (DLT) was grade 4 or grade 3 non-heme toxicity that prevented treatment for 2 weeks. Clinical/lab safety assessments, pharmacokinetics, leukocyte subsets, and serum cytokine levels were monitored. Results: 19 patients completed 4+ weeks of treatment, with 3+ patients at 0.04, 0.16, 0.32, 0.48, and 0.64 mg/kg/w. No DLTs occurred. Side effects included injection site reaction (78%), fever (61%), chills (57%), fatigue/malaise (57%), and myalgia (35%). Grade 3 toxicities possibly related to therapy were pain/nausea in one patient, hypoxia/chills in one patient (pre-existing COPD), and anemia in 2 patients. IMOxine regularly produced a lymphopenia 24 h after treatment consistent with cytokine-mediated lymphocyte margination. IMOxine typically increased the percentage of CD69+ T cells. Although plasma drug concentrations were dose proportional, immunology parameters appeared to plateau or decrease above 0.16 mg/kg/w. Nine patients had stable disease after 8 w of IMOxine treatment, and 4 had stable disease for at least 16 weeks. Of these 4, 1 with renal cell carcinoma had minor regression after 16 weeks and persisting currently through 40 weeks. Discontinuation in five patients was due to rapid disease progression after 1–5 doses of IMOxine, two were consent withdrawals, and three were symptomatic deterioration despite radiologically stable disease. Conclusions: IMOxine treatment was well tolerated at all doses. Effects were consistent with the immunological mechanism of action and clinical outcome was encouraging. A phase II monotherapy trial in renal cell carcinoma has been initiated. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Hybridon Hybridon

Spotlight on Omalizumab in Allergic Asthma1

Omalizumab (Xolair) is a humanized monoclonal antibody used in the treatment of adolescent and adult patients with moderate to severe allergic asthma inadequately controlled with inhaled corticosteroids (ICS). It selectively binds to circulating immunoglobulin E (IgE) and, thereby, prevents binding of IgE to mast cells and other effector cells. Without surface-bound IgE, these cells are unable to recognize allergens, thus preventing cellular activation by antigens and the subsequent allergic/asthmatic symptoms. Omalizumab decreases free serum IgE levels in a dose-dependent manner, reduces IgE receptor density on effector cells, and significantly improves airway inflammation parameters. Omalizumab is slowly absorbed after subcutaneous administration, and mean elimination half-life is 26 days, thus allowing infrequent administration of the drug. Omalizumab dosage is determined by bodyweight and pretreatment serum total IgE levels. Patients treated with subcutaneous omalizumab in clinical trials received a dosage that was approximately equal to 0.016 mg/kg/IgE (IU/mL) per 4 weeks. Thus, patients received 150 or 300 mg every 4 weeks, or 225, 300, or 375 mg every 2 weeks. In adults and adolescents (> or = 12 years of age) with moderate to severe allergic asthma, subcutaneous administration of omalizumab as add-on therapy with ICS improved the number of asthma exacerbations, rescue medication use, asthma symptom scores, and quality-of-life (QOL) scores compared with placebo during 28- and 32-week double-blind trials. In addition, concomitant ICS use was significantly decreased in patients receiving omalizumab, and in the two largest double-blind trials approximately 40% of omalizumab recipients completely withdrew from ICS therapy while maintaining effective asthma control. In general, results of extension studies showed that the beneficial effects of omalizumab were maintained over a total period of 52 weeks. Omalizumab was well tolerated as add-on therapy with ICS during treatment for up to 52 weeks. Common adverse events in clinical trials included injection site reaction, viral infection, upper respiratory tract infection, sinusitis, headache, and pharyngitis, although the incidence of adverse events with omalizumab was similar to that with placebo. In conclusion, omalizumab, as add-on therapy with ICS, is an effective and well tolerated agent for the treatment of moderate to severe allergic asthma in adolescents and adults. In addition to its symptomatic and QOL benefits, omalizumab therapy allows ICS dosage reduction or discontinuation of ICS in many patients. Comparisons of omalizumab with other asthma therapies have yet to be conducted; however, clinical efficacy and tolerability data indicate that omalizumab is a valuable option in the treatment of allergic asthma.

Omalizumab: a review of its use in the management of allergic asthma.

Omalizumab (Xolair) is a humanized monoclonal antibody used in the treatment of adolescent and adult patients with moderate to severe allergic asthma inadequately controlled with inhaled corticosteroids (ICS). It selectively binds to circulating immunoglobulin E (IgE) and, thereby, prevents binding of IgE to mast cells and other effector cells. Without surface-bound IgE, these cells are unable to recognize allergens, thus preventing cellular activation by antigens and the subsequent allergic/asthmatic symptoms. Omalizumab decreases free serum IgE levels in a dose-dependent manner, reduces IgE receptor density on effector cells, and significantly improves airway inflammation parameters. Omalizumab is slowly absorbed after subcutaneous administration, and mean elimination half-life is 26 days, thus allowing infrequent administration of the drug. Omalizumab dosage is determined by bodyweight and pretreatment serum total IgE levels. Patients treated with subcutaneous omalizumab in clinical trials received a dosage that was approximately equal to 0.016 mg/kg/IgE (IU/mL) per 4 weeks. Thus, patients received 150 or 300 mg every 4 weeks, or 225, 300, or 375 mg every 2 weeks. In adults and adolescents (> or =12 years of age) with moderate to severe allergic asthma, subcutaneous administration of omalizumab as add-on therapy with ICS improved the number of asthma exacerbations, rescue medication use, asthma symptom scores, and quality-of-life (QOL) scores compared with placebo during 28- and 32-week double-blind trials. In addition, concomitant ICS use was significantly decreased in patients receiving omalizumab, and in the two largest double-blind trials approximately 40% of omalizumab recipients completely withdrew from ICS therapy while maintaining effective asthma control. In general, results of extension studies showed that the beneficial effects of omalizumab were maintained over a total period of 52 weeks. Omalizumab was well tolerated as add-on therapy with ICS during treatment for up to 52 weeks. Common adverse events in clinical trials included injection site reaction, viral infection, upper respiratory tract infection, sinusitis, headache, and pharyngitis, although the incidence of adverse events with omalizumab was similar to that with placebo. Omalizumab, as add-on therapy with ICS, is an effective and well tolerated agent for the treatment of moderate to severe allergic asthma in adolescents and adults. In addition to its symptomatic and QOL benefits, omalizumab therapy allows ICS dosage reduction or discontinuation of ICS in many patients. Comparisons of omalizumab with other asthma therapies have yet to be conducted; however, clinical efficacy and tolerability data indicate that omalizumab is a valuable option in the treatment of allergic asthma.

Spotlight on etanercept in rheumatoid arthritis, psoriatic arthritis and juvenile rheumatoid arthritis.

Etanercept (Enbrel) is a subcutaneously administered biological response modifier that binds and inactivates tumour necrosis factor-alpha, a proinflammatory cytokine. In patients with early active rheumatoid arthritis, etanercept 25mg twice weekly was associated with a more rapid improvement in disease activity and a significantly greater cumulative response than methotrexate over 12 months of treatment in a randomised, double-blind trial. In addition, etanercept recipients showed a slower rate of radiographic progression and a more rapid improvement in quality of life than methotrexate recipients. The efficacy of etanercept was maintained at 3 years' follow-up. Etanercept was also significantly better than placebo at reducing disease activity in patients who had an inadequate response to previous treatment with disease-modifying antirheumatic drugs (DMARDs) in several well controlled trials. At study end (after 3 or 6 months' treatment), the percentage of patients achieving an American College of Rheumatology 20% (ACR20) response with etanercept (25mg or 16 mg/m(2) twice weekly) was 59-75% as monotherapy and 71% in combination with methotrexate; corresponding placebo response rates were 11-14% and 27%, respectively. Response has been maintained in patients who continued treatment for up to 5 years. In patients with psoriatic arthritis, etanercept 25mg twice weekly significantly reduced disease activity and improved skin lesions in two double-blind, placebo-controlled, 12- to 24-week trials. In the 24-week study, ACR20 response rates (50 vs 13%), psoriatic arthritis response rates (70 vs 23%) and the median improvement in skin lesions (33 vs 0%) were significantly greater in etanercept than in placebo recipients. In patients with polyarticular-course juvenile rheumatoid arthritis, etanercept resulted in improvements in all measures of disease activity and was significantly more effective than placebo at reducing disease flare. Eighty percent of patients receiving etanercept achieved a > or =30% reduction in disease activity over 7 months of treatment, and this was maintained for up to 2 years in a trial extension. Etanercept was generally well tolerated in children and adults in clinical trials; the most commonly occurring adverse effects included injection site reactions, infection, headache, rhinitis and dizziness. In conclusion, etanercept has emerged as an important new treatment option in inflammatory arthritis. Etanercept provides rapid and sustained improvements in disease activity in patients with early and DMARD-refractory rheumatoid arthritis and has been shown to inhibit radiographic progression in those with early disease. Well controlled studies have also demonstrated the efficacy of etanercept in patients with psoriatic arthritis or polyarticular-course juvenile rheumatoid arthritis.

Management of Rheumatoid Arthritis

Rheumatoid arthritis is associated with substantial costs to both the individual and society; costs increase as disease severity worsens. Current thinking is that disease-modifying antirheumatic drug (DMARD) therapy should be started as soon as possible after the diagnosis of rheumatoid arthritis and that patients should be offered the most effective treatment available. Etanercept is a soluble dimeric fusion protein comprising two copies of the extracellular ligand-binding domain of the human p75 receptor for tumour necrosis factor-α (TNFα) linked to the constant portion of human immunoglobulin G1. TNFα is thought to play an important role in the pathophysiology of rheumatoid arthritis; by binding the cytokine, etanercept blocks its biologic effects. In a 12-month double-blind, randomized study involving patients with early active rheumatoid arthritis, administration of subcutaneous etanercept 25mg twice weekly was associated with a more rapid and significantly greater overall response (assessed using American College of Rheumatology criteria) than oral methotrexate. In addition, compared with methotrexate, etanercept was associated with more rapid slowing of radiographic progression and a more rapid improvement in measures of health-related quality of life. The efficacy of etanercept was maintained at 3 years’ follow-up. Etanercept, alone or in combination with methotrexate, also showed sustained efficacy in three double-blind, randomized, placebo-controlled studies of 3 to 6 months’ duration involving patients with active rheumatoid arthritis who had not responded adequately to previous treatment with DMARDs. Etanercept was generally well tolerated in clinical trials (the most commonly occurring adverse events included injection site reactions, infection, headache, nausea, rhinitis, dizziness, pharyngitis and cough). The high cost of etanercept relative to traditional DMARDs may be justified if it can be shown to reduce long-term outcomes associated with rheumatoid arthritis, thereby reducing disease costs. Conclusion: Etanercept is an important new treatment option in rheumatoid arthritis. It provides a rapid and sustained reduction in disease activity and inhibits the progression of structural damage in patients with early active rheumatoid arthritis, with good tolerability. The improvement in disease activity and slowing of joint damage seen with etanercept was more rapid than that seen with methotrexate. In addition, etanercept, alone or in combination with methotrexate, is effective in the treatment of patients with active rheumatoid arthritis who have not responded adequately to previous DMARD therapy. It is anticipated that etanercept may also improve the long-term outcome of patients with rheumatoid arthritis and reduce the substantial economic burden imposed by the disease; however, more long-term data are needed to establish this.

Adrogolide HCl (ABT-431; DAS-431), a prodrug of the dopamine D1 receptor agonist, A-86929: preclinical pharmacology and clinical data.

Adrogolide (ABT-431; DAS-431) is a chemically stable prodrug that is converted rapidly (<1 min) in plasma to A-86929, a full agonist at dopamine D1 receptors. In in vitro functional assays, A-86929 is over 400 times more selective for dopamine D1 than D2 receptors. In rats with a unilateral loss of striatal dopamine, A-86929 produces contralateral rotations that are inhibited by dopamine D1 but not by dopamine D2 receptor antagonists. Adrogolide improves behavioral disability and locomotor activity scores in MPTP-lesioned marmosets, a model of Parkinson's disease (PD), and shows no tolerance upon repeated dosing for 28 days. In PD patients, intravenous (i.v.) adrogolide has antiparkinson efficacy equivalent to that of L-DOPA with a tendency towards a reduced liability to induce dyskinesia. The adverse events associated with its use were of mild-to-moderate severity and included injection site reaction, asthenia, headache, nausea, vomiting, postural hypotension, vasodilitation, and dizziness. Adrogolide can also attenuate the ability of cocaine to induce cocaine-seeking behavior and does not itself induce cocaine-seeking behavior in a rodent model of cocaine craving and relapse. In human cocaine abusers, i.v. adrogolide reduces cocaine craving and other cocaine-induced subjective effects. The results of animal abuse liability studies indicate that adrogolide is unlikely to have abuse potential in man. Adrogolide has also been reported to reverse haloperidol-induced cognitive deficits in monkeys, suggesting that it may be an effective treatment for the cognitive dysfunction associated with aging and disease. Adrogolide undergoes a high hepatic "first-pass" metabolism in man after oral dosing and, as a result, has a low oral bioavailability (approximately 4%). This limitation may potentially be circumvented by oral inhalation formulations for intrapulmonary delivery that greatly increase the bioavailability of adrogolide. As the first full dopamine D1 receptor agonist to show efficacy in PD patients and to reduce the craving and subjective effects of cocaine in cocaine abusers, adrogolide represents an important tool in understanding the pharmacotherapeutic potential of dopamine D1 receptor agonists.

Recombinant human interleukin-3 induces extramedullary hematopoiesis at subcutaneous injection sites in cynomolgus monkeys.

Parenteral administration of recombinant hematopoietic growth factors has been sporadically associated with cutaneous complications, including injection site reactions in humans and nonhuman primates. In this study, subcutaneous injection sites were evaluated from 12 cynomolgus monkeys administered a recombinant human interleukin-3 (rhIL-3) at dose levels of 0, 70, or 700 micrograms/kg daily for 18 days. Monkeys administered rhIL-3 developed small (0.5-1-cm-diameter), firm nodules at the subcutaneous injection sites. Histologically, these nodules from 4 of 8 rhIL-3-treated monkeys contained trilineage extramedullary hematopoiesis (EMH) represented by precursors of myeloid, erythroid, and megakaryocytic series cells. The lineage of hematopoietic cells was confirmed by histochemical and immunohistochemical methods. Hematopoietic cells of myeloid and megakaryocytic lineages were more common than erythroid cells. Of myeloid cells, immature eosinophils were more common, which usually formed small sheets or clusters in the panniculus and deep dermis. This report describes, for the first time, the occurrence of cutaneous EMH at the injection sites of recombinant hematopoietic growth factors, which should be differentiated from inflammation. We believe the cutaneous EMH was the exaggerated pharmacologic effect of rhIL-3.