Efficacy of a trivalent influenza vaccine against seasonal strains and against 2009 pandemic H1N1: A randomized, placebo-controlled trial.

BACKGROUND: Before pandemic H1N1 vaccines were available, the potential benefit of existing seasonal trivalent inactivated influenza vaccines (IIV3s) against influenza due to the 2009 pandemic H1N1 influenza strain was investigated, with conflicting results. This study assessed the efficacy of seasonal IIV3s against influenza due to 2008 and 2009 seasonal influenza strains and against the 2009 pandemic H1N1 strain. METHODS: This observer-blind, randomized, placebo-controlled study enrolled adults aged 18-64years during 2008 and 2009 in Australia and New Zealand. Participants were randomized 2:1 to receive IIV3 or placebo. The primary objective was to demonstrate the efficacy of IIV3 against laboratory-confirmed influenza. Participants reporting an influenza-like illness during the period from 14days after vaccination until 30 November of each study year were tested for influenza by real-time reverse transcription polymerase chain reaction. RESULTS: Over a study period of 2years, 15,044 participants were enrolled (mean age±standard deviation: 35.5±14.7years; 54.4% female). Vaccine efficacy of the 2008 and 2009 IIV3s against influenza due to any strain was 42% (95% confidence interval [CI]: 30%, 52%), whereas vaccine efficacy against influenza due to the vaccine-matched strains was 60% (95% CI: 44%, 72%). Vaccine efficacy of the 2009 IIV3 against influenza due to the 2009 pandemic H1N1 strain was 38% (95% CI: 19%, 53%). No vaccine-related deaths or serious adverse events were reported. Solicited local and systemic adverse events were more frequent in IIV3 recipients than placebo recipients (local: IIV3 74.6% vs placebo 20.4%, p<0.001; systemic: IIV3 46.6% vs placebo 39.1%, p<0.001). CONCLUSIONS: The 2008 and 2009 IIV3s were efficacious against influenza due to seasonal influenza strains and the 2009 IIV3 demonstrated moderate efficacy against influenza due to the 2009 pandemic H1N1 strain. Funded by CSL Limited, ClinicalTrials.gov identifier NCT00562484.

Investigating the Effect of a Single Infusion of Reconstituted High-Density Lipoprotein in Patients with Symptomatic Carotid Plaques.

BACKGROUND: Elevation of plasma high-density lipoprotein (HDL) cholesterol concentration reduces cardiovascular mortality and morbidity. HDLs have been shown to possess acute anti-inflammatory, antioxidant, and antithrombotic properties. We hypothesize that HDL therapy can acutely alter local and systemic manifestations of plaque instability. METHODS: Forty patients with early symptomatic carotid disease were randomized to either receive reconstituted HDL (rHDL) 40 mg/kg (n = 20) or placebo (n = 20). Carotid endarterectomies were performed 24 hr later. Plaques were obtained intraoperatively and used for measurement of thrombomodulatory genes expression. Plasma samples were collected before the infusion, 24 and 48 hr later to measure changes in systemic markers of plaque instability. RESULTS: No significant differences were noted in thrombomodulatory genes expression between the 2 groups. Systemic levels of tissue factor, matrix metalloproteinase 9 (MMP-9), and monocyte chemotactic factor-1 (MCP-1) were significantly reduced in the rHDL group. However, the effects on MMP-9 and MCP-1 were abolished in the immediate postoperative period. Although rHDL did not affect plasma interleukin-6 levels 24 hr following the infusion, it prevented the significant postoperative elevation seen in the placebo group. CONCLUSIONS: A single infusion of rHDL can acutely alter plasma biomarkers associated with plaque instability and cardiovascular morbidity.

A Phase 1 study of the safety, pharmacokinetics and anti-leukemic activity of the anti-CD123 monoclonal antibody CSL360 in relapsed, refractory or high-risk acute myeloid leukemia.

Acute myeloid leukemia (AML) blasts express high levels of interlekin-3 (IL-3) receptor-α (CD123). CSL360 is a recombinant, chimeric immunoglobulin G1 (IgG1), anti-CD123 monoclonal antibody (MoAb) that neutralizes IL-3 and demonstrates anti-leukemic activity in vitro. This phase 1 study assessed safety, pharmacokinetics and bioactivity of weekly intravenous CSL360 for 12 weeks in 40 patients with advanced AML across five dose levels (0.1-10.0 mg/kg). Other than mild infusion reactions, CSL360 was well tolerated. The maximal tolerated dose was not reached. The half-life was 4.9 days, and the area under the curve (AUC) and maximum concentration (Cmax) increased proportionally with dose. Doses ≥ 3.0 mg/kg resulted in complete saturation and down-regulation of CD123 and abolition of ex vivo proliferative responsiveness to IL-3, indicating adequate blockade of IL-3 signaling. Two patients responded, with one remaining in complete remission after 17 doses. CSL360 bound CD123 specifically, but did not induce anti-leukemic activity in most patients. While safe, MoAb blockade of CD123 function is insufficient as a therapeutic strategy.

High-dose chemotherapy with autologous stem-cell support as adjuvant therapy in breast cancer: overview of 15 randomized trials.

PURPOSE: Adjuvant high-dose chemotherapy (HDC) with autologous hematopoietic stem-cell transplantation (AHST) for high-risk primary breast cancer has not been shown to prolong survival. Individual trials have had limited power to show overall benefit or benefits within subsets. METHODS: We assembled individual patient data from 15 randomized trials that compared HDC versus control therapy without stem-cell support. Prospectively defined primary end points were relapse-free survival (RFS) and overall survival (OS). We compared the effect of HDC versus control by using log-rank tests and proportional hazards regression, and we adjusted for clinically relevant covariates. Subset analyses were by age, number of positive lymph nodes, tumor size, histology, hormone receptor (HmR) status, and human epidermal growth factor receptor 2 (HER2) status. RESULTS: Of 6,210 total patients (n = 3,118, HDC; n = 3,092 control), the median age was 46 years; 69% were premenopausal, 29% were postmenopausal, and 2% were unknown menopausal status; 49.5% were HmR positive; 33.5% were HmR negative, and 17% were unknown HmR status. The median follow-up was 6 years. After analysis was adjusted for covariates, HDC was found to prolong relapse-free survival (RFS; hazard ratio [HR], 0.87; 95% CI, 0.81 to 0.93; P < .001) but not overall survival (OS; HR, 0.94; 95% CI, 0.87 to 1.02; P = .13). For OS, no covariates had statistically significant interactions with treatment effect, and no subsets evinced a significant effect of HDC. Younger patients had a significantly better RFS on HDC than did older patients. CONCLUSION: Adjuvant HDC with AHST prolonged RFS in high-risk primary breast cancer compared with control, but this did not translate into a significant OS benefit. Whether HDC benefits patients in the context of targeted therapies is unknown.

Immunogenicity of a monovalent 2009 influenza A(H1N1) vaccine in infants and children: a randomized trial.

CONTEXT: In the ongoing influenza pandemic, a safe and effective vaccine against 2009 influenza A(H1N1) is needed for infants and children. OBJECTIVE: To assess the immunogenicity and safety of a 2009 influenza A(H1N1) vaccine in children. DESIGN, SETTING, AND PARTICIPANTS: Randomized, observer-blind, age-stratified, parallel group study assessing 2 doses of an inactivated, split-virus 2009 influenza A(H1N1) vaccine in 370 healthy infants and children aged 6 months to less than 9 years living in Australia. INTERVENTION: Intramuscular injection of 15 microg or 30 microg of hemagglutinin antigen dose of monovalent, unadjuvanted 2009 influenza A(H1N1) vaccine in a 2-dose regimen, administered 21 days apart. MAIN OUTCOME MEASURES: Hemagglutination inhibition assay to estimate the proportion of participants with antibody titers of 1:40 or greater, seroconversion, or a significant antibody titer increase, and factor increase in geometric mean titer. Assessments of solicited adverse events during 7 days and unsolicited adverse events for 21 days after each vaccination. RESULTS: Following the first dose of vaccine, antibody titers of 1:40 or greater were observed in 161 of 174 infants and children in the 15-microg group (92.5%; 95% confidence interval [CI], 87.6%-95.6%) and in 168 of 172 infants and children in the 30-microg group (97.7%; 95% CI, 94.2%-99.1%). Corresponding seroconversion rates were 86.8% (95% CI, 80.9%-91.0%) and 94.2% (95% CI, 89.6%-96.8%), and factor increases in geometric mean titer were 13.6 (95% CI, 11.8-15.6) and 18.3 (95% CI, 15.7-21.4). All participants demonstrated antibody titers of 1:40 or greater after the second vaccine dose. Immune responses were robust regardless of age, baseline serostatus, or seasonal influenza vaccination status. The majority of adverse events were mild to moderate in severity. CONCLUSION: One 15-microg dose of vaccine was immunogenic in infants and children starting at 6 months of age and vaccine-associated reactions were mild to moderate in severity. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00940108.

Safety and immunogenicity of an inactivated thimerosal-free influenza vaccine in infants and children.

OBJECTIVE: Few prospective studies of inactivated split virion influenza vaccine have been conducted in infants and children. Our objective was to evaluate the safety, reactogenicity and immunogenicity of a thimerosal-free inactivated influenza vaccine (Fluvax; CSL Limited, Parkville, Australia) in children aged 6 months to <9 years. METHODS: A prospective, open-label, phase III clinical trial was conducted in 298 healthy children previously unvaccinated with influenza, commencing in the Southern Hemisphere 2005 autumn. Participants were divided into two groups (Group A: > or =6 months to <3 years; Group B: > or =3 years to <9 years), and received two doses of the 2005 vaccine, and one dose of the 2006 vaccine one year later (Group A: 0.25 ml per dose; Group B: 0.5 ml per dose). Vaccine safety and reactogenicity was evaluated for 30 days after each dose. Immunogenicity was assessed using hemagglutination inhibition and single radial hemolysis assays. RESULTS: There were no withdrawals due to adverse events (AEs). The majority of solicited local and systemic AEs were of mild severity. A maximum intensity of severe was reported for injection site pain and fever by only 3.0% and 3.4% of participants, respectively. The vaccine was immunogenic for all antigens, with > or =95% of both younger and older children achieving seroprotection after dose 2. CONCLUSIONS: This thimerosal-free inactivated influenza vaccine had a favorable safety profile and was immunogenic in children aged > or =6 months and <9 years. Primary and booster vaccination produced consistently immunogenic responses including in children under 3 years of age receiving 0.25 ml doses of vaccine.

Response to a monovalent 2009 influenza A (H1N1) vaccine.

BACKGROUND: A novel 2009 influenza A (H1N1) virus is responsible for the first influenza pandemic in 41 years. A safe and effective vaccine is needed. A randomized, observer-blind, parallel-group trial evaluating two doses of an inactivated, split-virus 2009 H1N1 vaccine in healthy adults between the ages of 18 and 64 years is ongoing at a single site in Australia. METHODS: We evaluated the immunogenicity and safety of the vaccine after each of two scheduled doses, administered 21 days apart. A total of 240 subjects, equally divided into two age groups (<50 years and >or=50 years), were enrolled and underwent randomization to receive either 15 microg or 30 microg of hemagglutinin antigen by intramuscular injection. We measured antibody titers using hemagglutination-inhibition and microneutralization assays at baseline and 21 days after vaccination. The coprimary immunogenicity end points were the proportion of subjects with antibody titers of 1:40 or more on hemagglutination-inhibition assay, the proportion of subjects with either seroconversion or a significant increase in antibody titer, and the factor increase in the geometric mean titer. RESULTS: By day 21 after the first dose, antibody titers of 1:40 or more were observed in 114 of 120 subjects (95.0%) who received the 15-microg dose and in 106 of 119 subjects (89.1%) who received the 30-microg dose. A similar result was observed after the second dose of vaccine. No deaths, serious adverse events, or adverse events of special interest were reported. Local discomfort (e.g., injection-site tenderness or pain) was reported by 56.3% of subjects, and systemic symptoms (e.g., headache) by 53.8% of subjects after each dose. Nearly all events were mild to moderate in intensity. CONCLUSIONS: A single 15-microg dose of 2009 H1N1 vaccine was immunogenic in adults, with mild-to-moderate vaccine-associated reactions. (ClinicalTrials.gov number, NCT00938639).

Safety and immunogenicity of a prototype adjuvanted inactivated split-virus influenza A (H5N1) vaccine in infants and children.

OBJECTIVE: Highly pathogenic avian influenza A virus (H5N1) is a leading candidate for the next influenza pandemic, and infants and children may play an important role in transmission in a pandemic. Our objective was to evaluate the safety and immunogenicity of a prototype inactivated, aluminium adjuvanted, split-virus, clade 1 H5N1 vaccine (A/Vietnam/1194/2004/NIBRG-14) in infants and children aged > or =6 months to < 9 years. METHODS: Healthy infants and children (N=150) received two doses of 30 microg or 45 microg H5 HA with AlPO4 adjuvant 21 days apart. Serum samples were collected for virus microneutralisation (MN) and haemagglutination inhibition (HI) assays on Days 0, 21, and 42. Six-month antibody persistence following second vaccine dose was assessed by MN, and cross-reactive HI antibodies to a clade 2 variant strain (INDO5/RG2) were evaluated at Day 42. FINDINGS: Both formulations were well-tolerated. Two doses of 30 microg or 45 microg H5 HA formulations elicited strong immune responses by both MN (98-99% > or =1:20) and HI assays (95-100% > or =1:32), with 80-87% of children having MN antibody persistence (> or =1:20) up to 6 months post-vaccination. Additionally, robust cross-clade HI antibody responses were elicited following two doses. INTERPRETATION: Two doses of prototype 30 microg or 45 microg aluminium-adjuvanted, H5N1 vaccines were highly immunogenic and well-tolerated, with considerable antibody persistence 6 months after the primary vaccination course. Additional cross-clade HI antibody responses and an acceptable safety and tolerability profile support the use of the either candidate vaccine formulations in infants and children in the event of a pandemic.

Phase I and II randomised trials of the safety and immunogenicity of a prototype adjuvanted inactivated split-virus influenza A (H5N1) vaccine in healthy adults.

OBJECTIVE: The primary objective was to evaluate the safety and immunogenicity of a prototype inactivated, split-virus H5N1 (avian influenza A) vaccine. A secondary objective was to assess the cross-reactivity of immune responses to two variant clade 2 H5N1 strains. METHODS: In two randomised, dose comparison, parallel assignment, multicentre trials conducted in Australia, healthy adult volunteers received two doses of 7.5 microg or 15 microg H5 haemagglutinin (HA) vaccine+/-AlPO4 adjuvant (phase I trial; N=400) or two doses of 30 microg or 45 microg H5 HA with AlPO4 adjuvant (phase II trial; N=400). Revaccination with a booster dose was offered 6 months after dose 2 (phase I trial only). Main outcome measures were the change in immunogenicity at each follow-up visit from baseline, measured using HA inhibition (HI) and virus microneutralisation (MN) assays, and the frequency and nature of adverse events (AEs). Computer generated tables were used to randomly allocate treatments; participants and investigators were blinded to treatment allocation. FINDINGS: All formulations were well-tolerated; no unexpected serious adverse events were reported. Two doses of 30 microg or 45 microg H5 HA adjuvanted formulations elicited the highest immune responses, with considerable MN antibody (>or=1:20) persistence up to 6 months post-vaccination. The 7.5 and 15 microg formulations (+/-adjuvant) were less immunogenic than the higher dose formulations; HI and MN antibody titres decreased to near pre-vaccination levels at 6 months but were restored to post-dose 2 levels after the booster dose. Immune responses in the phase I trial demonstrated modest levels of cross-protective MN antibodies against two currently circulating, distinct clade 2 H5N1 strains. INTERPRETATION: Two doses of prototype 30 microg or 45 microg aluminium-adjuvanted, clade 1 H5N1 vaccines were immunogenic and well-tolerated with considerable 6-month antibody persistence. The prototype H5N1 vaccine also elicited modest levels of cross-protective MN antibodies against variant clade 2 H5N1 strains [ClinicalTrials.gov identifiers: NCT00136331, NCT00320346; FUNDING: CSL Limited, Australia].

Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial.

CONTEXT: High-density lipoprotein (HDL) cholesterol is an inverse predictor of coronary atherosclerotic disease. Preliminary data have suggested that HDL infusions can induce atherosclerosis regression. OBJECTIVE: To investigate the effects of reconstituted HDL on plaque burden as assessed by intravascular ultrasound (IVUS). DESIGN AND SETTING: A randomized placebo-controlled trial was conducted at 17 centers in Canada. Intravascular ultrasound was performed to assess coronary atheroma at baseline and 2 to 3 weeks after the last study infusion. PATIENTS: Between July 2005 and October 2006, 183 patients had a baseline IVUS examination and of those, 145 had evaluable serial IVUS examinations after 6 weeks. INTERVENTION: Sixty patients were randomly assigned to receive 4 weekly infusions of placebo (saline), 111 to receive 40 mg/kg of reconstituted HDL (CSL-111); and 12 to receive 80 mg/kg of CSL-111. MAIN OUTCOME MEASURES: The primary efficacy parameter was the percentage change in atheroma volume. Nominal changes in plaque volume and plaque characterization index on IVUS and coronary score on quantitative coronary angiography were also prespecified end points. RESULTS: The higher-dosage CSL-111 treatment group was discontinued early because of liver function test abnormalities. The percentage change in atheroma volume was -3.4% with CSL-111 and -1.6% for placebo (P = .48 between groups, P<.001 vs baseline for CSL-111). The nominal change in plaque volume was -5.3 mm3 with CSL-111 and -2.3 mm3 with placebo (P = .39 between groups, P<.001 vs baseline for CSL-111). The mean changes in plaque characterization index on IVUS (-0.0097 for CSL-111 and 0.0128 with placebo) and mean changes in coronary score (-0.039 mm for CSL-111 and -0.071 mm with placebo) on quantitative coronary angiography were significantly different between groups (P = .01 and P =.03, respectively). Administration of CSL-111 40 mg/kg was associated with mild, self-limiting transaminase elevation but was clinically well tolerated. CONCLUSIONS: Short-term infusions of reconstituted HDL resulted in no significant reductions in percentage change in atheroma volume or nominal change in plaque volume compared with placebo but did result in statistically significant improvement in the plaque characterization index and coronary score on quantitative coronary angiography. Elevation of HDL remains a valid target in vascular disease and further studies of HDL infusions, including trials with clinical end points, appear warranted. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00225719

High dose chemotherapy for poor prognosis breast cancer: systematic review and meta-analysis.

BACKGROUND: High dose chemotherapy with autologous transplantation of bone marrow or peripheral stem cells (autograft) has been considered promising for treating poor prognosis breast cancer. We reviewed the relevant evidence. METHODS: We included randomised controlled trials comparing high dose chemotherapy and autograft with conventional chemotherapy for women with early poor prognosis breast cancer. We searched medical databases (Cochrane Library, MEDLINE, EMBASE), websites (co-operative cancer research groups, American Society of Clinical Oncologists) and citations of articles found, to September 2006. Where appropriate, data were pooled to obtain a relative risk, using a fixed effects model. Clinical, methodological and statistical heterogeneity were examined with sensitivity analyses. FINDINGS: Thirteen trials with 5064 women were included. There was a significant benefit in event-free survival for the high dose group at three years (RR 1.19 (95% CI 1.06, 1.19)) and four years (RR 1.24 (95% CI 1.03, 1.50)) and at five years this benefit approached statistical significance (RR 1.06 (95% CI 1.00, 1.13)). Overall survival rates were not significantly different at any stage of follow up. There were significantly more treatment-related deaths on the high dose arm (RR 8.58 (95% CI 4.13, 17.80)). Morbidity was higher in the high dose group but there was no significant difference in the incidence of second cancers. The high dose group reported significantly worse quality of life immediately after treatment, but there were few differences by one year. INTERPRETATION: There is insufficient evidence supporting routine use of high dose chemotherapy with autograft for treating early poor prognosis breast cancer.

Multicycle dose-intensive chemotherapy for women with high-risk primary breast cancer: results of International Breast Cancer Study Group Trial 15-95.

PURPOSE: To compare adjuvant dose-intensive epirubicin and cyclophosphamide chemotherapy administered with filgrastim and progenitor cell support (DI-EC) with standard-dose anthracycline-based chemotherapy (SD-CT) for patients with early-stage breast cancer and a high risk of relapse, defined as stage II disease with 10 or more positive axillary nodes; or an estrogen receptor-negative or stage III tumor with five or more positive axillary nodes. PATIENTS AND METHODS: Three hundred forty-four patients were randomized after surgery to receive seven cycles of SD-CT over 22 weeks, or three cycles of DI-EC (epirubicin 200 mg/m2 plus cyclophosphamide 4 gm/m2 with filgrastim and progenitor cell support) over 6 weeks. All patients were assigned tamoxifen at the completion of chemotherapy. The primary end point was disease-free survival (DFS). RESULTS: After a median follow-up of 5.8 years (range, 3 to 8.4 years), 188 DFS events had occurred (DI-EC, 86 events; SD-CT, 102 events). The 5-year DFS was 52% for DI-EC and 43% for SD-CT, with hazard ratio of DI-EC compared with SD-CT of 0.77 (95% CI, 0.58 to 1.02; P = .07). The 5-year overall survival was 70% for DI-EC and 61% for SD-CT, with a hazard ratio of 0.79 (95% CI, 0.56 to 1.11; P = .17). There were eight cases (5%) of anthracycline-induced cardiomyopathy (two fatal) among those who received DI-EC. Women with hormone receptor-positive tumors benefited significantly from DI-EC. CONCLUSION: There was a trend in favor of DI-EC with respect to disease-free survival. A larger trial or meta-analysis will be required to reveal the true effect of dose-intensive therapy.

Phase 1 study of HPV16-specific immunotherapy with E6E7 fusion protein and ISCOMATRIX adjuvant in women with cervical intraepithelial neoplasia.

PURPOSE: Persistent infection of cervical epithelium with "high risk" human papillomavirus (HPV) results in cervical intraepithelial neoplasia (CIN) from which squamous cancer of the cervix can arise. A study was undertaken to evaluate the safety and immunogenicity of an HPV16 immunotherapeutic consisting of a mixture of HPV16 E6E7 fusion protein and ISCOMATRIX adjuvant (HPV16 Immunotherapeutic) for patients with CIN. EXPERIMENTAL DESIGN: Patients with CIN (n = 31) were recruited to a randomised blinded placebo controlled dose ranging study of immunotherapy. RESULTS: Immunotherapy was well tolerated. Immunised subjects developed HPV16 E6E7 specific immunity. Antibody, delayed type hypersensitivity, in vitro cytokine release, and CD8 T cell responses to E6 and E7 proteins were each significantly greater in the immunised subjects than in placebo recipients. Loss of HPV16 DNA from the cervix was observed in some vaccine and placebo recipients. CONCLUSIONS: The HPV16 Immunotherapeutic comprising HPV16E6E7 fusion protein and ISCOMATRIX adjuvant is safe and induces vaccine antigen specific cell mediated immunity.

A phase I study of recombinant human leukemia inhibitory factor in patients with advanced cancer.

PURPOSE: Leukemia inhibitory factor (LIF) is a pleiotropic molecule of the interleukin 6 family of cytokines. We aimed to examine the safety, pharmacokinetics, and biological effects of recombinant human LIF (rhLIF, emfilermin) in patients with advanced cancer. EXPERIMENTAL DESIGN: In stage 1 of the study, 34 patients received rhLIF or placebo (3:1 ratio) at doses of 0.25-16.0 micro g/kg/day or 4.0 micro g/kg three times daily for 7 days. In stage 2, 40 patients received rhLIF or placebo, either once daily for 14 days commencing the day after chemotherapy (0.25-8.0 micro g/kg/day) or for 7 days commencing the day before chemotherapy (4.0 micro g/kg three times daily). The chemotherapy was cisplatin 75 mg/m(2) and paclitaxel 135 mg/m(2). RESULTS: In stage 1, platelet counts increased in most patients, including those who received placebo. Blood progenitor cells increased in response to rhLIF. In stage 2, platelet recovery to baseline levels was earlier for patients receiving higher doses of rhLIF (>/=4.0 micro g/kg/day; P = 0.02). The neutrophil nadir after chemotherapy was less severe in patients receiving >/=4.0 micro g/kg/day of rhLIF. In stages 1 and 2, increases in C reactive protein were seen at higher doses. Several patients developed evidence of autonomic dysfunction, in particular impotence and episodic hypotension. The dose-limiting toxicities were hypotension and rigors. Pharmacokinetic studies demonstrated a short half-life (1-5 h) independent of dose. CONCLUSIONS: We demonstrated a biological effect of rhLIF on blood progenitor cells, C reactive protein levels, and hemopoietic recovery after chemotherapy.

The impact of thrombopoietin on clinical practice.

Prevention of hemorrhage secondary to thrombocytopenia has generally been managed by the transfusion of platelets. The need for such transfusion is related to the depth and duration of "critical" thrombocytopenia, a level that until recently was hotly debated. However a number of clinical trials have established that transfusion at a platelet count greater than 10 x 10(9)/L was safe in the absence of factors associated with increased tendency to bleed. Trying to predict which patients are at risk of bleeding due to thrombocytopenia has proven difficult outside of those scenarios that inevitably cause severe thrombocytopenia, such as treatment of leukemia and myeloablative chemotherapy with stem cell support. Models have been proposed but have yet to be validated. Of greater importance is the need for proof that intensive treatment of solid tumours with growth tactor support leads to improved outcomes. The discovery of platelet growth factors raised expectations that an effective method for abrogating thrombocytopenia would be soon available in the clinic. The cytokines initially described were pleiotropic in nature, and stimulation of platelet production was generally modest. However, one of these agents, interleukin-11, was successfully shown to reduce the incidence of severe thrombocytopenia in patients receiving dose-intensive chemotherapy, and has now received approval from the FDA for this purpose. Initial clinical trials of thrombopoietin (TPO), the central regulator of megakaryocytopoiesis and thrombopoiesis, and its analogues showed these agents to be the most potent stimulators of thrombopoiesis and to be associated with few adverse effects. They have also been shown to enhance platelet recovery after chemotherapy, but early results from trials investigating their ability to prevent severe thrombocytopenia associated with the treatment of leukemia and bone marrow transplantation have been disappointing. In addition, subcutaneous administration of one of these agents, megakaryocyte growth and development factor, has been shown to induce the formation of antibodies that neutralize native TPO and cause thrombocytopenia. TPO remains a promising therapeutic agent, however its potential application is more limited than initially anticipated, and there are a number of obstacles to overcome before it finds an importance use in the clinic.

Development of pancytopenia with neutralizing antibodies to thrombopoietin after multicycle chemotherapy supported by megakaryocyte growth and development factor.

Clinical trials of thrombopoietin (TPO), the central regulator of megakaryocytopoiesis, have revealed few side effects associated with its use. We here report a case of pancytopenia associated with the development of neutralizing antibodies to TPO that occurred in a patient who had undergone multicycle chemotherapy with multiple cycles of subcutaneous administration of pegylated recombinant human megakaryocyte growth and development factor. Samples of the patient's bone marrow showed trilineage hypoplasia with absence of myeloid, erythroid, and megakaryocyte progenitor cells but with elevated endogenous levels of erythropoietin, granulocyte colony-stimulating factor, and stem-cell factor. To our knowledge, this is the first report of an aplastic anemia-like syndrome associated with neutralizing antibodies to TPO.