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Biomedical subjects

Jane L Liesveld

Publications and source records attributed to Jane L Liesveld.

14 recordsLinked to original sources
PubMed2006

A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia.

Outcomes for older adults with acute myelogenous leukemia (AML) are poor due to both disease and host-related factors. In this phase 2 study, we tested the oral farnesyltransferase inhibitor tipifarnib in 158 older adults with previously untreated, poor-risk AML. The median age was 74 years, and a majority of patients had antecedent myelodysplastic syndrome. Complete remission (CR) was achieved in 22 patients (14%); partial remission or hematologic improvement occurred in 15 patients, for an overall response rate of 23%. The median duration of CR was 7.3 months and the median survival of complete responders was 18 months. Adverse karyotype, age 75 years or older, and poor performance status correlated negatively with survival. Early death in the absence of progressive disease was rare, and drug-related nonhematologic serious adverse events were observed in 74 patients (47%). Inhibition of farnesylation of the surrogate protein HDJ-2 occurred in the large majority of marrow samples tested. Baseline levels of phosphorylated mitogen-activated protein kinase and AKT did not correlate with clinical response. Tipifarnib is active and well tolerated in older adults with poor-risk AML and may impart a survival advantage in those patients who experience a clinical response.

Adult↗
PubMed2005

Apoptosis and complement-mediated lysis of myeloma cells by polyclonal rabbit antithymocyte globulin.

Current monoclonal antibody therapies for multiple myeloma have had limited success, perhaps due to narrow target specificity. We have previously described the ability of polyclonal rabbit antithymocyte globulin (rATG) to induce caspase- and cathepsin-mediated apoptosis in human B and plasma cells. We now extend this observation to myeloma cells. Complement independent cell death was measured after addition of rATG (1-1000 microg/mL) to cultures of myeloma cell lines or primary CD138+ isolates from patient bone marrow aspirates. rATG induced significant levels of apoptosis in myeloma cells as assayed by caspase induction, annexin V binding, subdiploid DNA fragmentation, plasma-membrane permeability, and loss of mitochondrial-membrane potential. Addition of complement greatly augmented myeloma-cell death. Binding of rATG to individual myeloma cell-surface proteins, primarily CD38, CD52, CD126, and CD138, was demonstrated by competitive inhibition experiments with targeted monoclonal antibodies. Three pathways of cell death were identified involving caspase activation, cathepsin D, and the genistein sensitive tyrosine kinase pathway. Fab'2 fragments of rATG had reduced proapoptotic activity, which was restored by coincubation with Fc fragments, and anti-CD32 or anti-CD64 antibodies. We conclude that rATG is an effective agent for in vitro induction of apoptosis in multiple myeloma, and that exploratory clinical trials may be warranted.

Animals↗
PubMed2005

Outcome of ethnic minorities with acute or chronic leukemia treated with hematopoietic stem-cell transplantation in the United States.

PURPOSE: We previously reported a higher risk of mortality among Hispanics after allogeneic hematopoietic stem-cell transplantation (HSCT). However, it is not known how specific post-transplantation events (acute or chronic graft-versus-host disease [GVHD], treatment-related mortality [TRM], and relapse) may explain mortality differences. The purpose of this study was to examine the relationship between ethnicity and post-transplantation events and determine their net effect on survival. PATIENTS AND METHODS: We identified 3,028 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or chronic myeloid leukemia reported to the International Bone Marrow Transplant Registry between 1990 and 2000 who received an HLA-identical sibling HSCT after a myeloablative conditioning regimen in the United States. There were 2,418 white patients (80%) and 610 ethnic minority patients (20%), of whom 251 were black (8%), 122 were Asian (4%), and 237 were Hispanic (8%). Cox proportional hazards regression was used to compare outcomes between whites and ethnic minorities while adjusting for other significant clinical factors. RESULTS: No statistically significant differences in the risk of acute or chronic GVHD, TRM, or relapse were found between whites and any ethnic minority group. However, Hispanics had higher risks of treatment failure (death or relapse; relative risk [RR] = 1.30; 95% CI, 1.08 to 1.54; P = .004) and overall mortality (RR = 1.23; 95% CI, 1.03 to 1.47; P = .02). CONCLUSION: The higher risks of treatment failure and mortality among Hispanics may be the net result of modest but not statistically significant increases in both relapse and TRM and cannot be accounted for by any single transplantation-related complication. Further studies should examine the role of social, economic, and cultural factors.

Acute Disease↗
PubMed2005

The use of AMD3100 plus G-CSF for autologous hematopoietic progenitor cell mobilization is superior to G-CSF alone.

Hematopoietic progenitor cells (HPCs) traffic to and are retained in the marrow through the trophic effects of the chemokine stromal cell-derived factor-1alpha (SDF-1alpha) binding to its receptor, CXC chemokine receptor 4 (CXCR4). AMD3100 reversibly inhibits SDF-1alpha/CXCR4 binding, and AMD3100 administration mobilizes CD34(+) cells into the circulation. We therefore tested the hypotheses that the combination of AMD3100 plus granulocyte colony-stimulating factor (G-CSF) (hereafter A + G) would be superior to G-CSF alone (hereafter G) in mobilizing hematopoietic progenitor cells (HPCs) and that A + G-mobilized cells would engraft as well as G-mobilized cells. The primary objective was to determine whether patients mobilized more progenitor cells per unit of blood volume of apheresis after A + G administration versus G alone. Secondary objectives were to determine whether patients mobilized with A + G compared with G alone required fewer apheresis procedures to reach the target level at least 5 x 10(6) CD34(+) cells/kg for transplantation and to determine whether patients mobilized with A + G had at least a 90% success rate of autologous transplantation as assessed by neutrophil engraftment by day 21. Each patient served as his or her own control in a sequential mobilization design. All study objectives were met without significant toxicity. The results demonstrate that the combination of A + G is generally safe, effective, and superior to G alone for autologous HPC mobilization.

Adolescent↗
PubMed2005

Acute myelogenous leukemia--microenvironment interactions: role of endothelial cells and proteasome inhibition.

How leukemia progenitors interact with marrow microenvironment components is poorly understood. In this work, the effects of endothelial coculture on acute myelogenous leukemia (AML) blast survival is examined as are the effects of endothelial coculture on the impact of a cytotoxic agent such as cytarabine. Similar to marrow stromal cells, endothelial cells are able to increase survival and proliferation of AML blasts and to partially protect against cytarabine effects. The proteasome inhibitor, bortezomib, has inhibitory effects in multiple myeloma in part through effects on marrow stromal cells. Bortezomib has been found to inhibit AML blast survival. Such inhibition is less, however, in the presence of endothelial monolayers. Furthermore, AML blast transmigration through human umbilical vein endothelial cells is inhibited by bortezomib. These studies demonstrate that AML is subject to influence of endothelial cells and of agents such as bortezomib which have potential impact on AML interaction with the microenvironmental niche.

Apoptosis↗
PubMed2004

A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome.

Bone marrow transplantation (BMT) can cure myelodysplastic syndrome (MDS), although transplantation carries significant risks of morbidity and mortality. Because the optimal timing of HLA-matched BMT for MDS is unknown, we constructed a Markov model to examine 3 transplantation strategies for newly diagnosed MDS: transplantation at diagnosis, transplantation at leukemic progression, and transplantation at an interval from diagnosis but prior to leukemic progression. Analyses using individual patient risk-assessment data from transplantation and nontransplantation registries were performed for all 4 International Prognostic Scoring System (IPSS) risk groups with adjustments for quality of life (QoL). For low and intermediate-1 IPSS groups, delayed transplantation maximized overall survival. Transplantation prior to leukemic transformation was associated with a greater number of life years than transplantation at the time of leukemic progression. In a cohort of patients under the age of 40 years, an even more marked survival advantage for delayed transplantation was noted. For intermediate-2 and high IPSS groups, transplantation at diagnosis maximized overall survival. No changes in the optimal transplantation strategies were noted when QoL adjustments were incorporated. For low- and intermediate-1-risk MDS, delayed BMT is associated with maximal life expectancy, whereas immediate transplantation for intermediate-2- and high-risk disease is associated with maximal life expectancy.

Adolescent↗
PubMed2004

The hematopoietic stem cell in myelodysplasia.

The mechanisms underlying hematopoietic stem cell or progenitor cell abnormalities in myelodysplastic syndromes (MDSs) remain poorly characterized. Current evidence exists for multiple intrinsic and extrinsic influences upon the stem cell in these disorders. These influences are outlined in this review and include: stem cell characteristics in MDSs, as compared with those in acute myelogenous leukemia; the role of increased apoptosis; the role of signaling pathway abnormalities; the influences of immune modulation; and the effect of stromal cells and stromal cell cytokine production. Despite numerous studies that have examined these factors, how they converge to produce a situation in which accelerated proliferation and accelerated death occur simultaneously remains largely an unexplored area. It is anticipated that future studies that focus on well-characterized and purified progenitor populations in these disorders will elucidate the process by which ineffective hematopoiesis results from the influences of stem cell abnormalities versus abnormalities in the stem cell's microenvironmental and immunologic milieu.

Animals↗
PubMed2003

A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group.

The optimal induction for older adults with acute myeloid leukemia (AML) is unknown. Several anthracyclines have been proposed, but the data remain equivocal. Additionally, few prospective trials of priming with hematopoietic growth factors to cycle leukemia cells prior to induction chemotherapy have been conducted. Three hundred and sixty-two older adults with previously untreated AML were randomized to either daunorubicin, idarubicin or mitoxantrone with a standard dose of cytarabine as induction therapy. In addition, 245 patients were also randomized to receive granulocyte-macrophage colony-stimulating factor (GM-CSF) or placebo beginning 2 days prior to induction chemotherapy and continuing until marrow aplasia. No difference was observed in the disease-free overall survival or in toxicity among patients receiving any of the 3 induction regimens or among those receiving growth factor or placebo for priming. However, the complete remission rate for the first 113 analyzable patients, who did not participate in the priming study and started induction therapy 3 to 5 days earlier than those who did, was significantly higher (50% versus 38%; P =.03). None of the anthracyclines is associated with improved outcome in older adults. Priming with hematopoietic growth factor did not improve response when compared with placebo. Furthermore, delaying induction therapy in older adults may lead to a lower complete remission rate.

Aged↗
PubMed2003

Flavonoid effects on normal and leukemic cells.

Quercetin and flavopiridol, both flavonoids which influence oxidative milieu, proliferation, and apoptosis of various cell types, were examined for their effects on acute myelogenous leukemic cells and normal progenitors. Both quercetin and flavopiridol inhibited the growth and viability of various acute myelogenous leukemia (AML) cell lines and AML blasts isolated afresh from patients with AML of various subtypes. The effects on inhibition of proliferation and decreased viability were also significant in normal CD34+ cells isolated from normal marrow donors. In certain AML cases, the effects of flavopiridol appeared to be mediated through activation of caspase 3, offering one possible mechanism for the apoptosis evident after exposure to flavopiridol as measured by annexin V expression. These flavonoid compounds might find use in various therapeutic settings in AML.

Adult↗
PubMed2002

Optimal cytokine stimulation for the enhanced generation of leukemic dendritic cells in short-term culture.

Dendritic cells (DCs) are professional antigen presenting cells derived from myeloid or lymphoid precursors. Functional DCs have been generated from the malignant counterpart of these precursor cells. Herein, we describe the generation of DCs from different leukemias and determine the optimal culture conditions with minimal manipulation. Primary leukemic cells were cultured for 1, 3, and 5 days in 11 different cytokine combinations and analyzed for the expression of a mature DC phenotype. Optimal growth and DC characteristics were obtained with GM-CSF, FL, and SCF in 3-5 day cultures, suggesting a practical strategy for the immunotherapy of leukemia.

Acute Disease↗
PubMed2002

Oral valacyclovir versus intravenous acyclovir in preventing herpes simplex virus infections in autologous stem cell transplant recipients.

Patients who are seropositive for herpes simplex virus (HSV) and are undergoing autologous marrow or peripheral blood stem cell transplantation require prophylaxis for HSV infection. Most prophylaxis regimens have used intravenous acyclovir (ACY). Oral valacyclovir (VAL), the L-valyl ester of ACY, can be used to achieve plasma concentrations equivalent to levels achieved with intravenous ACY. In this study, adults undergoing autologous stem cell transplantation were randomized to receive ACY, 250 mg/m2 intravenously (IV) every 12 hours from day 0 to engraftment, or VAL, 1 g orally every 12 hours from day 0 to engraftment. The primary study objective was to compare cost of HSV prophylaxis between study groups. Thirty patients were randomized to receive either oral VAL (n = 14) or IV ACY (n = 16) prophylaxis. Mean pharmacy cost of HSV prophylaxis in the patient group randomized to IV ACY was $1080 versus $320 for the group randomized initially to VAL. This study demonstrates the feasibility and significant cost savings of using oral VAL for HSV prophylaxis.

Acyclovir↗
PubMedDate not supplied

The effect of using music therapy with relaxation imagery in the management of patients undergoing bone marrow transplantation: a pilot feasibility study.

CONTEXT: Bone marrow/stem cell transplantation is becoming an increasingly common treatment for a variety of hematologic disorders. The treatment process is not benign. Both physiologic and psychological regimen-related side effects are common, painful, and even life threatening. Music therapy is the prescribed use of music to aid in the prevention or amelioration of physical, psychological, or cognitive problems. Relaxation imagery, as used in this study, consisted of simple visualization and direct imagery-based suggestions. The mechanism of action of the intervention is hypothesized to be reduction of the stress response through neuroendocrine pathways. OBJECTIVE: To determine the feasibility of providing a combined music therapy and relaxation imagery intervention to patients on a bone marrow transplant (BMT) unit and to examine the effects on the frequency and intensity of pain and nausea, the two most common side effects associated with transplantation. DESIGN: Case controlled study. SETTING: University hospital-based bone marrow transplant unit serving patients of all ages. PARTICIPANTS: Transplant recipients aged 4 years or older. INTERVENTION: 45-minute music-assisted relaxation and relaxation imagery sessions provided twice a week by a trained music therapist from date of enrollment into the study to discharge. MAIN OUTCOME MEASURES: Pre/post music/relaxation imagery intervention measures of pain and nausea using a visual analog scale; determination of time-to-engraftment.

Adolescent↗