ALBERT

Description: HIV infected patients may be at increased risk for VTE, as shown by case reports, and a recent retrospective, longitudinal medical record review of approximately 42,000 HIV-infected individuals (Sullivan, 2000). There is a well documented association between acute and chronic inflammation and activation of the hemostatic system. Inflammatory cytokines such as TNF alpha, IL-1 and IL-6 have been shown to activate coagulation via the Tissue Factor pathway. Inflammation can also result in a decrease in functional Protein S, and in an increase in Factor VIII coagulant protein. We hypothesized that the inflammatory state associated with more advanced HIV disease would be associated with hemostatic activation, and clinical development of VTE over time. Methods: We assayed plasma for factor VIII activity levels, functional protein S activity, presence of lupus anticoagulant, and C reactive protein levels in a group of 96 HIV infected women and 50 HIV negative women from the Women’s Interagency HIV Study (WIHS). All assays were performed blinded to subjects HIV status. This cross sectional sample of WIHS participants from the Los Angeles site were studied at their second study visit (1994-5). The sample was selected to represent the following groups: (1) History of clinical AIDS, CD 4〈 200; (2) CD4 〈 200, no clinical AIDS; (3) HIV positive, CD4 〉 200; HIV-negative. Pts were excluded if they were taking any hormones or contraceptives; had been pregnant within 6 weeks of study; had any acute, active infection at the time of study visit. Hemostatic data were correlated with HIV viral load, CD4 cell count, history of clinical AIDS, history of anti-retroviral and other medication use, and levels of serum and plasma C reactive protein (CRP). Results are depicted below for median (inter-quartile range) values, adjusted for age: Group Protein S Factor VIII Serum CRP# 1. Clinical AIDS, CD4 〈 200 46* (40,65) 212* (174,253) 2.0 (0.5,4.8) 2. No Clinical AIDS, CD4 〈 200 62^ (55,67) 196+ (150, 234) 0.8 (0.7,2.7) 3. HIV+, No Clinical AIDS, CD4 〉 200 67.5 (59,83) 154^ (111,202) 0.9 (0.4, 3.3) 4. HIV Negative 75.5 (66,85) 116.5 (97,154) 1.85 (0.8, 5.1) Models were adjusted for age. Groups are significantly different from HIV negative participants (group 4) at the indicated p-values, determined using Scheffe adjustment * p

Description: Background: Anemia is common in patients (pts) infected with the Human Immunodeficiency Virus (HIV). In these pts, anemia is associated with diminished quality of life (QoL) and is an independent prognostic factor for mortality. Aranesp® (darbepoetin-alfa) is a recombinant erythropoiesis-stimulating protein with extended serum half-life allowing for less frequent dosing than conventional recombinant erythropoietin. We studied Aranesp® in anemic HIV-positive pts to evaluate safety, hemoglobin (Hgb) response, and quality of life (QoL). Methods: Entry criteria included HIV infection, Hgb 〈 11.5 g/dL, and adequate renal and liver function. Patients with anemia due to bleeding, malignancy, B12, folate, or iron deficiency were excluded. Aranesp® 3.0 mg/kg was given sc every 2 weeks (Q2W) for 24 weeks. Treatment response was defined as Hgb increase of ≥ 1.5 g/dL from baseline sustained for ≥ 4 weeks duration at any time during the study. If no response by wk 8, Aranesp® was escalated to 5.0 μg/kg. Results: Thirteen female and 10 male pts have been enrolled to date. Median age was 43 years (range 27–67), median entry Hgb was 10.6 g/dL (range 8.6–11.5), and median CD4 count was 197 cells/mm3 (range 29–821). Nine (39%) pts had a prior clinical AIDS-defining illness or opportunistic infection, 19 (87%) pts received concurrent HAART therapy; 11 (58%) were receiving a zidovudine- containing regimen with either combivir (n=6) or trizivir (n=5). Aranesp® was well tolerated. The only treatment-associated side effect was mild pain at the injection site. Pts who received ≥ 8 wks of Aranesp® were analyzed (n=20). 17 of the 20 pts (85%) had a Hgb response (median duration 12+ weeks [range 4+ to 22+]). One of these pts required a dose escalation. Evaluation of change in QoL using a Linear Analog Scale in 20 evaluable patients showed a mean improvement in energy level (+23.2 mm), activity level (+19.8 mm) and overall QoL (+15.5 mm) over the first 8 wks of treatment. Conclusions: In HIV-infected pts with anemia, Aranesp® at a dose of 3.0 mg/kg Q2W is well tolerated, is associated with a Hgb response in the majority of pts, effectively maintains Hgb levels, and improves QoL. Further work is on-going.

Description: Introduction: Large randomized trials in pediatric ALL show that multiple doses of E.Coli asparaginase (ASP) given throughout post remission phase are associated with improved outcome. ASP is routinely incorporated into most front line adult ALL protocols. PEG-asparaginase (PEG-ASP) is E.coli ASP, which is linked to polyethylene glycol reducing the risk of hypersensitivity reactions and prolonging the half life compared to the native forms. In children multiple doses of PEG-ASP produce less neutralizing antibodies than equivalent doses of native E. coli ASP with similar toxicity (Avramis Blood 99:1986Avramis Blood 99:2002). Information on PEG-ASP in adults is very limited. In a previous study we showed that in adult ALL, a single IV dose of PEG-ASP given at induction produces a long duration of serum ASP enzymatic activity and concomitant asparagine depletion with similar toxicity to equivalent multiple doses of E.coli ASP. We currently report in adults the pharmacokinetics (PK), antibody production and toxicity of multiple doses of PEG-ASP given throughout the treatment of patients with newly diagnosed previously untreated ALL. Methods: We used a modified augmented BFM ALL protocol consisting of 8 cycles of multi-agent chemotherapy followed by maintenance. PEG-ASP (2000 U/m2/dose) is given IV once on day 15 of the following cycles (total 6 doses): induction phase I (cycle 1), induction phase II (cycle 2), two cycles of consolidation (cycles 3 and 6), and two cycles of delayed re-induction (cycles 5 and 8). Serum samples were taken weekly for three weeks for ASP enzymatic activity after PEG-ASP dosing in induction phase 1 (dose 1) and in delayed re-inductions I and II (doses 4 and 6, respectively). Results: 18 patients aged 19–57 (median 28) years with newly diagnosed ALL (precursor B cell - 14, T -4) were studied. All 18 patients (100%) achieved a CR after induction phase I. Six patients discontinued the protocol because of undergoing allogeneic stem-cell transplantation. The number of doses of PEG-ASP was: all 6 doses- 4 pts, 4-3 pts., 2–5 pts., 1– 6 pts. Total number of doses was 52. T ½ was 7±4.7 days (n=18) after the fist dose increasing to 11.9±5.9 days (n=11) after dose 4 and 6. In the first cycle the AUC and MRT were lower while the Vd, Vdss and total clearance (Clt) were higher compared to the subsequent cycles. The change in PK parameters over time is most likely due to Michaelis-Menten (M-M) rate-limiting step on the elimination of the drug. Peak serum levels did not change significantly between the cycles. Anti-ASP antibodies were not detected in any patient-cycles. Grade 3/4 toxicities were hyperbilirubinemia - 3 pts (3 doses), elevated liver enzymes - 10 pts (13 doses), hyperglycemia - 7 pts (10 doses), allergy, pancreatitis, neuropathy, and fatigue - 1 pt (1 dose) each. All toxicities were reversible. We saw no pattern of increasing toxicity in subsequent doses of PEG-ASP. Only two patients had relapsed (median follow up of 15 months). Conclusion: multiple doses of PEG-ASP can be given IV to adults (age

Description: Background: Thrombocytopenia is a common condition among HIV-infected individuals, however its significance is unclear, particularly among women. Two previous studies, one consisting mostly of men (Sullivan PS, et al. J Acquir Immune Defic Syndr.1997;14:374–379) and one of hemophiliacs (Ehmann WC, et al. Am J Hematol.1997; 54:296–300), have suggested that low platelet count is associated with decreased survival. Methods: The Women’s Interagency HIV Study (WIHS) is a long-term prospective cohort study of HIV-infected women and HIV-negative women that is being conducted at six urban sites across the United States. 1,990 HIV-infected women and 553 HIV-negative women are included in this report. These women are seen every six months; the median follow-up time is 7.5 years. We conducted extensive multivariate analysis using both generalized estimating equations and Cox proportional hazards models in order to determine the predictors of thrombocytopenia and the role of platelet count in mortality among women being followed as part of this study. Results: At baseline, 15% of HIV-positive women were thrombocytopenic versus 1.6% of HIV-negative women (p

Description: BACKGROUND: ATN-224 is an orally available, small molecule containing molybdenum (Mo) that specifically binds copper. ATN-224 inhibits multiple signaling pathways important to angiogenesis and tumor growth such as pathways mediated by growth factors, including vascular endothelial growth and epidermal growth factors and signaling molecules such as protein kinase B (PKB/Akt) and nuclear factor kappa B. ATN-224 exerts these effects through the inhibition of the enzyme copper-zinc superoxide dismutase (SOD1) in endothelial and tumor cells. Activity has been seen in a variety of animal tumor models including bortezomib-resistant myeloma. METHODS: Adult pts with recurrent or refractory hematologic malignanies or for which no standard therapy exists were enrolled. Pts had to have adequate performance status (PS 0–2) and have adequate hematologic and organ function. Pts were monitored for safety and efficacy and blood samples for pharmacokinetic and biomarker determinations were taken at specified intervals. At least 3 pts were to be enrolled at each dose level starting at 120 mg/day. Pts who left the study prior to 28 days for reasons other than toxicity were to be replaced. If 1 pt developed dose-limiting toxicity (DLT) as defined by the protocol, the cohort was to be expanded to up to 6 pts. Maximum tolerated dose (MTD) was defined as the highest dose where no more than 1 of 6 pts had DLT. Dose adjustments were made on the basis of toxicity and serum ceruloplasmin (Cp), a surrogate marker for total body copper. Pts received a loading dose for 2 weeks and then doses were titrated to keep Cp between 5 and 15 mg/dL. RESULTS: 17 pts (53% female), ages 43–79 (mean 63), with PS 0 or 1 were entered. 8 pts had myeloma, 5 leukemia, 3 lymphoma, and 1 myelodysplastic syndrome. Because of rapid progression in 5 pts who were replaced and 1 DLT (Grade [Gr] 4 neutropenia, Gr 3 anemia), 11 pts were entered in the 1st cohort. With information from a companion study in pts with solid tumors, the dose for the next cohort was increased to 300 mg. 1 of 6 pts had DLT (Gr 4 neutropenia). No further cohorts were entered as 300 mg/day was determined as MTD from the companion study. Pts who received long-acting antacids were found to have higher Mo concentrations than those without, so the protocol was amended to require all pts to receive daily antacid. Dose-dependent inhibition of SOD in red blood cells (a surrogate tissue for tumor) was observed. Major adverse events included reversible Gr 4 neutropenia, Gr 3 anemia, and Gr 3 thrombocytopenia. Gr 3 fatigue, which was DLT in the solid tumor study, was not observed in this trial. Mild to moderate symptoms such as gastrointestinal disorders, headache and lightheadedness were also observed. There were no responses but 1 pt with leukemia had stable disease for 5 months and a pt with myeloma had stable disease for 4.5 months. CONCLUSION: ATN-224, an antiangiogenesis and antitumor agent with a novel mechanism of action, has manageable, reversible toxicity. The dose recommended for Phase II studies is 300 mg/day with dose adjustment starting at 2 weeks to maintain Cp at 5–15 mg/dL.