ALBERT

Description: Postmenopausal women have an increased risk of cardiovascular disease, and heart disease is the leading cause of death in postmenopausal American women. Conventional hormone replacement therapy has been shown to result in an increase in thrombotic events in large prospective clinical trials including HERS I, and the recently halted Women’s Health Initiative. One possible mechanism for this observed increase is the unfavorable net effects of conjugated equine estrogens and medroxyprogesterone acetate on the hemostatic balance and inflammatory factors. An estimated 50 million American women are peri or postmenopausal and clinical therapies for menopausal symptoms remain a significant challenge in light of the known thrombotic risks. In this prospective blinded study, we examined the short-term effect of topical progesterone cream on menopausal symptom relief in 30 healthy postmenopausal women. Potential adverse effects of topical progesterone on hemostatic and inflammatory factors and cortisol levels were also examined. Subjects were randomized to first receive either 20 mg of topical progesterone cream or placebo cream for 4 weeks. Following a subsequent 4-week washout period, subjects were crossed over to either placebo cream or active drug for an additional 4-week period. In each case, progesterone and cortisol levels were monitored by salivary sampling. Baseline values, 4-week follow-up values and end-of-study values were also obtained for the Greene Climacteric Scale, total factor VII:C, factor VIIa, factor V, fibrinogen, antithrombin, PAI-1, CRP, TNFα, and IL-6. For subjects receiving 20 mg of topical progesterone cream for 4 weeks, Greene Climacteric Scale scores were consistently and significantly improved (decreased) over baseline, demonstrating significant relief from menopausal symptoms. In addition, in a subpopulation of hypercortisolemic women, topical progesterone was associated with a favorable decrease in nocturnal cortisol. Surprisingly, and in sharp contrast to earlier studies with conventional hormone replacement therapy, topical progesterone had no effect on any of the hemostatic components examined: total factor VII:C, factor VIIa, factor V, fibrinogen, antithrombin, and PAI-1 levels were all unchanged. Levels of CRP, TNFα and IL-6 also remained unchanged. From this study we conclude that administration of topical progesterone cream at a daily dose of 20 mg significantly relieves menopausal symptoms in postmenopausal women without adversely altering prothrombotic potential. Since the thrombotic complications that are typically observed with conventional hormone replacement therapy do not seem to occur with topical progesterone, this treatment should be seriously considered as an effective and safe alternative clinical therapy for women suffering from menopausal symptoms.

Description: Background: Talabostat (PT-100), an orally available inhibitor of dipeptidyl peptidases, is in Phase 2 studies for B-cell malignancies and solid tumors. Talabostat increases production of cytokines and chemokines in lymph nodes and spleen, stimulating both adaptive and innate immune responses (Adams S, Cancer Research, 2004;64:5471). Talabostat may thus enhance the antibody-dependent cytotoxicity of MAbs such as rituximab. Methods: This is a Phase 1 study to evaluate the safety and activity of talabostat and rituximab in patients with indolent NHL who did not respond or progressed following rituximab. Rituximab 375mg/m2 was administered weekly x 4. Total daily doses of talabostat 400μg (n=6), 600μg (n=3), or 800μg (n=6) were administered BID for 6 days following each dose of rituximab. Cytokines and chemokines were assessed pre-, 2, and 6 hours post-talabostat on Days 1, 6, 13, 20, and 27. Flow cytometry was performed at baseline and Day 28. Clinical and laboratory evaluations were performed at specified times. Adverse events (AEs) were graded per NCI-CTC and recorded throughout the study. Disease assessments were performed on Days 28 and 84. Results: 11 men and 4 women aged 48–82 with NHL (n=10) or SLL/CLL (n=5) have been treated. 9 patients completed the 28-day study: 4 at 400μg, 1 at 600μg, and 4 at 800μg. Enrollment continues at 400μg/day. The most frequent AEs have been edema (67%), nausea (47%), dizziness (40%), hypotension (33%), fatigue (33%), vomiting (33%), constipation (33%), thrombocytopenia (27%), and weight gain (27%). Grade 3 toxicities include: dizziness, myopathy (400μg/day), and 2 events of thrombocytopenia (600μg/day). Grade 3 peripheral edema, myalgia, dehydration, electrolyte imbalance, hypereosinophilia, elevated CPK (primarily CK-MM), and rhabdomyolysis were seen in 2/6 patients at 800μg/day; these events were DLTs. One partial response (PR) lasting 7 months was seen in one patient (800μg/day). A PR was seen in a second patient at 800μg/day but did not meet the strict NCI-WG criteria for response. Elevations in cytokines 〉ULN were reported across all doses following talabostat: G-CSF (13/15), IL-1β (10/15), IL-2 (7/15), IL-6 (8/15), IL-8 (8/15), IL-10 (11/15), TNF-α (11/15), and IFN-γ (3/15). At Day 28 or early termination, CD20 was decreased in most (12/15) patients. Increases were seen in the percentage of CD3 (12/15), CD3/4 (11/15) and CD3/8 (9/15). In all 5 patients with SLL/CLL, CD5+/CD20+ was

Description: Background: T cells can be activated and expanded ex vivo using the Xcellerate™ Process, in which peripheral blood mononuclear cells (PBMC) are incubated with anti-CD3 and anti-CD28 antibody-coated magnetic beads (Xcyte™-Dynabeads®). In an ongoing trial of Xcellerated T Cells in subjects with chronic lymphocytic leukemia, marked and sustained reductions in lymphadenopathy and splenomegaly were observed (Wierda et al., ASCO 2004). Increases in neutrophil, platelet and NK cell counts were also documented. This study is designed to determine if similar effects can be observed in subjects with indolent non-Hodgkin’s lymphoma (NHL). Methods: Subjects must have indolent NHL (follicular, small lymphocytic, marginal zone, or mantle cell lymphoma), have relapsed or refractory disease, and have received at least 1 but not more than 4 prior treatment regimens. PBMC are collected by leukapheresis for the Xcellerate Process, and subjects subsequently receive two infusions of 20–60 x 109 Xcellerated T Cells separated by 6–8 weeks. Approximately 40 subjects will be treated. Results: Seven subjects have been enrolled and Xcellerated T Cells have been manufactured in 5 subjects to date. T cells expanded 181.8 ± 88.5 fold and the final product was 〉99.0 ± 0.0% T cells (mean + SD). One subject with small lymphocytic lymphoma has been treated with two infusions of 38.6 x 109 Xcellerated T Cells. There have been no serious adverse events to date. Following the first treatment, the lymphocyte count increased from 1.8 x 109/L to 2.9 x 109/L on Day 28. The neutrophil count also increased from 2.9 x 109/L to 5.5 x 109/L six weeks following infusion. The subject had a significant reduction in cervical lymphadenopathy and a slight decrease in bulky mesenteric lymphadenopathy six weeks following the first infusion. Conclusions: Xcellerated T Cells can be manufactured in subjects with indolent NHL. Treatment leads to significant increases in T cell and neutrophil counts. Preliminary data suggest a reduction in peripheral lymphadenopathy. Data on additional subjects will be presented.

Description: A case of erythremic myelosis is described which was characterized by a severe anemia from the beginning. There was irregular remitting fever, splenomegaly and hepatomegaly. The peripheral blood showed immature erythroblasts, granulopenia and thrombocytopenia. The bone marrow showed hyperplasia of erythropoiesis with maturation arrest, and a persistent megaloblastic type of nucleus in abnormal red cells. There was also a well defined proliferation of the reticulo-endothelial system. The course was that of the subacute variety of erythremic myelosis, but it began with an acute phase and ended acutely. A remission of nearly three months without transfusion followed a transfusion of fresh blood. While this may be coincidental with a spontaneous remission we feel that it is probable that a maturation factor in the fresh blood was responsible. For this reason we feel it is reasonable to suppose that other cases of erythremic myelosis will benefit more from fresh blood than from stored blood; and, as in our case, the inevitable fatal outcome after two months or less can be postponed for an appreciable number of months.

Description: Hemochromatosis is a common disorder characterized by excess iron absorption and accumulation of iron in tissues. Usually hemochromatosis is inherited in an autosomal recessive pattern and is caused by mutations in the HFE gene. Less common non-HFE–related forms of hemochromatosis have been reported and are caused by mutations in the transferrin receptor 2 gene and in a gene localized to chromosome 1q. Autosomal dominant forms of hemochromatosis have also been described. Recently, 2 mutations in theferroportin1 gene, which encodes the iron transport protein ferroportin1, have been implicated in families with autosomal dominant hemochromatosis from the Netherlands and Italy. We report the finding of a novel mutation (V162del) in ferroportin1 in an Australian family with autosomal dominant hemochromatosis. We propose that this mutation disrupts the function of the ferroportin1 protein, leading to impaired iron homeostasis and iron overload.