Matthew L. Sherman

Efficacy and Safety of Gemtuzumab Ozogamicin in Patients With CD33-Positive Acute Myeloid Leukemia in First Relapse

PURPOSE Three open-label, multicenter trials were conducted to evaluate the efficacy and safety of single-agent Mylotarg (gemtuzumab ozogamicin; CMA-676; Wyeth Laboratories, Philadelphia, PA), an antibody-targeted chemotherapy agent, in patients with CD33-positive acute myeloid leukemia (AML) in untreated first relapse. PATIENTS AND METHODS The study population comprised 142 patients with AML in first relapse with no history of an antecedent hematologic disorder and a median age of 61 years. All patients received Mylotarg as a 2-hour intravenous infusion, at a dose of 9 mg/m(2), at 2-week intervals for two doses. Patients were evaluated for remission, survival, and treatment-emergent adverse events. RESULTS Thirty percent of patients treated with Mylotarg obtained remission as characterized by 5% or less blasts in the marrow, recovery of neutrophils to at least 1,500/microL, and RBC and platelet transfusion independence. Although patients treated with Mylotarg had relatively high incidences of myelosuppression, grade 3 or 4 hyperbilirubinemia (23%), and elevated hepatic transaminase levels (17%), the incidences of grade 3 or 4 mucositis (4%) and infections (28%) were relatively low. There was a low incidence of severe nausea and vomiting (11%) and no treatment-related cardiotoxicity, cerebellar toxicity, or alopecia. Many patients received Mylotarg on an outpatient basis (38% and 41% of patients for the first and second doses, respectively). Among the 142 patients, the median total duration of hospitalization was 24 days; 16% of patients required 7 days of hospitalization or less. CONCLUSION Administration of the antibody-targeted chemotherapy agent Mylotarg to patients with CD33-positive AML in first relapse induces complete remissions with what appears to be a favorable safety profile.

Ionizing radiation induces expression and binding activity of the nuclear factor kappa B.

Recent studies have demonstrated that treatment of mammalian cells with ionizing radiation is associated with activation of gene expression. Although the signal transduction pathways stimulated by ionizing radiation remain unclear, our previous findings indicate that radiation induces specific genes at the transcriptional level. The present work has examined the effects of ionizing radiation on the transcription factor NF-kappa B. The results demonstrate that ionizing radiation activates DNA binding of nuclear factor (NF)kappa B. This effect was detectable at 2 grays (Gy) and reached a maximum at 5-20 Gy. At a dose of 20 Gy, the increase in NF-kappa B binding activity was maximal at 2-4 h and then declined to pretreatment levels. The results also demonstrate that ionizing radiation transiently increases NF-kappa B mRNA levels. However, the finding that induction of NF-kappa B binding to DNA occurs in the presence of cycloheximide indicates that ionizing radiation activates preexisting NF-kappa B protein. NF-kappa B exists as a cytoplasmic protein before activation. Thus, our results suggest that ionizing radiation induces transduction pathways which include cytoplasmic signaling events.

Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence

In this study, the authors analyzed the efficacy and safety of gemtuzumab ozogamicin (GO) (Mylotarg®), an antibody‐targeted chemotherapy for CD33‐positive acute myeloid leukemia (AML).

Single-Dose, Randomized, Double-Blind, Placebo-Controlled Study of ACE-011 (ActRIIA-IgG1) in Postmenopausal Women

The effects of ACE‐011 on safety, pharmacokinetics, and bone biomarkers were evaluated in healthy, postmenopausal women. Our data indicate that ACE‐011 results in a sustained increase in biomarkers of bone formation and reduction in markers of bone resorption. The activin type IIA receptor (ActRIIA) is the high‐affinity receptor for activin. ACE‐011 is a dimeric fusion protein consisting of the extracellular domain of the human ActRIIA linked to the Fc portion of human IgG1. ACE‐011 binds to activin, preventing activin from binding endogenous receptors. A randomized, double‐blind, placebo‐controlled study was conducted to evaluate the safety and tolerability of ACE‐011. Forty‐eight healthy, postmenopausal women were randomized to receive either a single dose of ACE‐011 or placebo and were followed for 4 mo. Dose levels ranged from 0.01 to 3.0 mg/kg intravenously and from 0.03 to 0.1 mg/kg subcutaneously. Safety and pharmacokinetic (PK) analyses and the biological activity of ACE‐011, as assessed by markers of bone turnover, and follicle stimulating hormone (FSH) levels were measured. No serious adverse events (AEs) were reported. AEs were generally mild and transient. The PK of ACE‐011 was linear over the dose range studied, with a mean half‐life of 24–32 days. The absorption after subcutaneous dosing was essentially complete. ACE‐011 caused a rapid and sustained dose‐dependent increase in serum levels of bone‐specific alkaline phosphatase (BSALP) and a dose‐dependent decrease in C‐terminal type 1 collagen telopeptide (CTX) and TRACP‐5b levels. There was also a dose‐dependent decrease in serum FSH levels consistent with inhibition of activin. ACE‐011 is a novel agent with biological evidence of both an increase in bone formation and a decrease in bone resorption. ACE‐011 may be an effective therapy in a variety of diseases involving bone loss.

Regulation of tumor necrosis factor gene expression by ionizing radiation in human myeloid leukemia cells and peripheral blood monocytes.

Previous studies have demonstrated that ionizing radiation induces the expression of certain cytokines, such as TNF alpha/cachectin. However, there is presently no available information regarding the molecular mechanisms responsible for the regulation of cytokine gene expression by ionizing radiation. In this report, we describe the regulation of the TNF gene by ionizing radiation in human myeloid leukemia cells. The increase in TNF transcripts by x rays was both time- and dose-dependent as determined by Northern blot analysis. Similar findings were obtained in human peripheral blood monocytes. Transcriptional run-on analyses have demonstrated that ionizing radiation stimulates the rate of TNF gene transcription. Furthermore, induction of TNF mRNA was increased in the absence of protein synthesis. In contrast, ionizing radiation had little effect on the half-life of TNF transcripts. These findings indicate that the increase in TNF mRNA observed after irradiation is regulated by transcriptional mechanisms and suggest that production of this cytokine by myeloid cells may play a role in the pathophysiologic effects of ionizing radiation.

A single ascending‐dose study of muscle regulator ace‐031 in healthy volunteers

ACE‐031 is a soluble form of activin receptor type IIB (ActRIIB). ACE‐031 promotes muscle growth by binding to myostatin and other negative regulators of muscle mass.

Transcriptional and posttranscriptional regulation of macrophage-specific colony stimulating factor gene expression by tumor necrosis factor. Involvement of arachidonic acid metabolites.

The effects of tumor necrosis factor (TNF) on the regulation of macrophage-specific colony stimulating factor (CSF-1) gene expression have been studied in HL-60 cells during monocytic differentiation. CSF-1 transcripts were undetectable in uninduced HL-60 cells, reached maximal levels by 3 h of exposure to TNF, and returned to that of control cells by 24 h. Transcriptional run-on analysis demonstrated that exposure to TNF stimulated the rate of CSF-1 gene transcription by 6.4-fold. The combination of a protein synthesis inhibitor, cycloheximide, and TNF increased levels of CSF-1 mRNA compared with treatment by TNF alone. We also studied the signal transduction mechanisms responsible for regulating TNF-induced CSF-1 mRNA levels. Both 4-bromophenacyl bromide and quinacrine, inhibitors of phospholipase A2 activity, blocked TNF-induced increases in CSF-1 transcripts in a concentration-dependent manner, while caffeic acid and nordihydroguaiaretic acid, inhibitors of the 5-lipoxygenase pathway, had no detectable effect on induction of CSF-1 RNA. PGE2 or dibutyryl cAMP treatment of HL-60 cells in the presence of TNF blocked the expression of CSF-1 mRNA in a dose-dependent manner. These findings suggest that the increase in CSF-1 RNA observed during TNF treatment is regulated, at least in part, by both transcriptional and posttranscriptional mechanisms, and that PGE2 and cAMP regulate transcriptional activation of the CSF-1 gene by TNF.

Posttranscriptional stabilization of c-fms mRNA by a labile protein during human monocytic differentiation.

The c-fms proto-oncogene encodes a transmembrane glycoprotein that is closely related or identical to the receptor for the monocyte colony-stimulating factor CSF-1. The present studies examined the mechanisms responsible for the regulation of c-fms gene expression during human monocytic differentiation. Levels of c-fms mRNA were undetectable in HL-60 promyelocytic leukemia cells, while 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced monocytic differentiation of these cells was associated with the appearance of these transcripts. Run-on transcription assays demonstrated that the c-fms gene was transcriptionally active in uninduced HL-60 cells and that the rate of transcription was unchanged after TPA treatment. These findings suggested that c-fms mRNA levels in HL-60 cells are controlled by posttranscriptional mechanisms. The half-life of c-fms transcripts in TPA-induced HL-60 cells was found to be at least 6 h, while inhibition of protein synthesis with cycloheximide (CHX) decreased this half-life to 4 h. Moreover, inhibition of protein synthesis was associated with decreases in c-fms mRNA levels and a block in the induction of c-fms transcripts by TPA. These findings indicated that the c-fms transcript is stabilized by a labile protein. In contrast to HL-60 cells, c-fms mRNA is constitutively expressed in resting human monocytes and is down-regulated by treatment of these cells with TPA. Run-on assays demonstrated that TPA-induced downregulation of c-fms mRNA levels in monocytes occurred at the posttranscriptional level. Moreover, the results demonstrate that levels of c-fms mRNA are regulated posttranscriptionally by a labile protein. In this regard, the half-life of the c-fms transcript was 6.1 h in monocytes, while treatment of these cells with CHX decreased the half-life to 30 min. Furthermore, this effect of CHX occurred in the absence of changes in the rate of c-fms gene transcription. Together, these findings indicate that c-fms gene expression is regulated at a posttranscriptional level both in HL-60 cells induced to differentiate along the monocytic lineage and in human monocytes. The findings also indicate that levels of c-fms mRNA are regulated by the synthesis of a labile protein which is involved in stabilization of the c-fms transcript.

A phase I trial of recombinant human tumor necrosis factor and interferon-gamma: effects of combination cytokine administration in vivo.

The combination of tumor necrosis factor (TNF) and interferon-gamma has synergistic bioactivity in numerous preclinical model systems. We have tested this potential synergism in vivo by administration of both cytokines to patients with advanced cancer using overlapping 24-hour continuous intravenous (IV) infusions in a phase I trial. Thirty-six patients were treated with a fixed dose of interferon-gamma (200 micrograms/m2/d) with interpatient dose escalation of TNF (from 5 to 205 micrograms/m2/d). The dose-limiting toxicity at the maximal-tolerated dose (MTD) of TNF (205 micrograms/m2) with interferon-gamma was hypotension. Other toxicities noted included an influenza-like syndrome, transient decreases in circulating leukocyte and platelet counts, subclinical evidence of disseminated intravascular coagulation, and the sporadic occurrence of acute pulmonary toxicity. The recommended phase II dose for this combination schedule is TNF, 136 micrograms/m2, with interferon-gamma, 200 micrograms/m2. The addition of interferon-gamma to TNF resulted in a greater than three-fold increase in toxicity compared with TNF administered as a single agent, supporting the hypothesis that the combination of these cytokines may induce synergistic effects in vivo.

Down-regulation of tumor necrosis factor expression by pentoxifylline in cancer patients: A pilot study

The wasting syndrome (cachexia) characterized by anorexia, malaise, and weight loss is observed in many patients with cancer or chronic infection. The excessive levels of tumor necrosis factor-α (TNF)/cachectin reported in 50% of cancer patients exhibiting clinically active disease may therefore mediate, at least in part, the cachexia associated with malignancy. Pentoxifylline, a substituted methylxanthine approved for treatment of intermittent claudication, has been shown in preclinical studies to down-regulate TNF RNA expression as well as TNF activity. We report that pentoxifylline suppressed TNF RNA levels on all three occasions in patients with initially elevated levels of TNF RNA. Pentoxifylline did not suppress TNF RNA to subnormal levels in all five patients with initially normal TNF RNA levels. Four patients reported an increased sense of well-being, improved appetite and ability to perform the activities of daily living. Two of these five patients with normal TNF levels each had a weight gain of more than 5% after 3 weeks of pentoxifylline therapy suggesting that, although TNF may be important in the pathogenesis of cancer cachexia, other anorexia-producing cytokines that are potentially affected by pentoxifylline may also be involved. No severe adverse effects were observed. Taken together these findings suggest that pentoxifylline can down-regulate TNF expression and improve the sense of well-being in cancer patients. A larger study with a randomized, double-blind, placebo-controlled design and more sophisticated estimates of quality of life will be needed to confirm these observations.