Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This phase 2 study evaluated the efficacy and safety of the oral farnesyltransferase inhibitor tipifarnib in adults with refractory or relapsed acute myeloid leukemia (AML). Patients (n=252) received tipifarnib 600 mg twice a day for 21 days in 28-day cycles. Median age was 62 years; 99 (39%) patients were 65 years or older. Eleven (4%) of 252 patients achieved complete remission (CR) or complete remission with incomplete platelet recovery (CRp; 9 CR and 2 CRp). Nineteen patients (8%), including those who achieved CR/CRp, achieved a reduction in bone marrow blasts to less than 5% blasts. Bone marrow blasts were reduced more than 50% in an additional 8 patients (total = 27; 11%). Median survival was 369 days for patients who achieved CR/CRp. Myelosuppression was the most common adverse event. The most common nonhematologic toxicities were fever, nausea, and hypokalemia. Single-agent treatment with tipifarnib induced durable CR/CRp, which was associated with prolonged survival, in some patients with refractory or relapsed AML. The response rate observed in this heavily pretreated group of patients suggests the requirement to enhance the response rate either by combining tipifarnib with other active agents or determining factors that are predictive of response.
 ...
PMID:A phase 2 study of the oral farnesyltransferase inhibitor tipifarnib in patients with refractory or relapsed acute myeloid leukemia. 1735 Nov 10

At present, there is no method available to predict response to farnesyltransferase inhibitors (FTIs). We analyzed gene expression profiles from the bone marrow of patients from a phase 2 study of the FTI tipifarnib in older adults with previously untreated acute myeloid leukemia (AML). The RASGRP1/APTX gene expression ratio was found to predict response to tipifarnib with the greatest accuracy using a "leave one out" cross validation (LOOCV; 96%). RASGRP1 is a guanine nucleotide exchange factor that activates RAS, while APTX (aprataxin) is involved in DNA excision repair. The utility of this classifier for predicting response to tipifarnib was validated in an independent set of 58 samples from relapsed or refractory AML, with a negative predictive value (NPV) and positive predictive value (PPV) of 92% and 28%, respectively (odds ratio of 4.4). The classifier also predicted for improved overall survival (154 vs 56 days; P < .001), which was independent of other covariates, including a previously described prognostic gene expression classifier. Therefore, these data indicate that a 2-gene expression assay may have utility in categorizing a population of patients with AML who are more likely to respond to tipifarnib.
 ...
PMID:A 2-gene classifier for predicting response to the farnesyltransferase inhibitor tipifarnib in acute myeloid leukemia. 1816 Jun 67

Treatment of older patients with acute myeloid leukemia (AML) represents a significant challenge. There is little evidence that outcomes are improving for patients subjected to conventional intensive treatment. In addition, there is a large population of patients who are not considered fit for a more intensive treatment approach, and treatment options are limited for these patients. As molecular mechanisms and characteristics of the disease become clearer, they represent potential targets for therapy. One such mechanism is the process of farnesylation, which is required for the activation of RAS proteins and potentially other deranged pathways. The first farnesyltransferase inhibitor (FTI) to undergo assessment in AML is tipifarnib, which has achieved a complete remission in 4% of patients who have relapsed and in 15% of untreated elderly patients. Responses were not restricted to patients with RAS protein mutations and the treatment was well tolerated in general. Several randomized comparative and combination trials have been set up that will establish the position of tipifarnib in the treatment of AML.
 ...
PMID:Tipifarnib in acute myeloid leukemia. 1817 65

While acute myeloid leukemia (AML) is significantly less common than acute lymphoblastic leukemia (ALL) in childhood, it is significantly more deadly with only half as many children likely to be cured with standard therapy. In addition, the typical treatment for AML is among the most toxic of treatments for pediatric cancer; it includes intensive multiagent chemotherapy and, often, hematopoietic stem cell transplantation. Given the poor prognosis of pediatric AML and the significant toxicity of standard AML therapy, novel therapies are needed. Improved understanding of the molecular and cellular biology of leukemia has facilitated the development of molecularly targeted therapies. In this article, we review progress to date with agents that are showing promise in the treatment of pediatric AML including targeted immunoconjugates, inhibitors of signaling molecules (e.g. FMS-like tyrosine kinase 3 [FLT3], farnesyltransferase, and mammalian target of rapamycin [mTOR]), agents that target epigenetic regulation of gene expression (DNA methyltransferase inhibitors and histone deacetylase inhibitors), and proteasome inhibitors. For the specific agents in each of these classes, we summarize the published preclinical data and the clinical trials that have been completed, are in progress, or are being planned for children with AML. Finally, we discuss potential challenges to the success of molecularly targeted therapy including demonstrating adequate targeting of leukemia stem cells, developing synergistic and tolerable combinations of agents, and designing adequately powered clinical trials to test efficacy in molecularly defined subsets of patients.
 ...
PMID:Molecularly targeted therapies for pediatric acute myeloid leukemia: progress to date. 1834 18

Novel strategies are required for treatment of acute myeloid leukaemia (AML) and higher risk myelodysplastic syndrome (MDS) patients who are not eligible for intensive chemotherapy and/or allogenic stem cell transplantation. As activating RAS mutations are frequent in these diseases, one novel approach, consisting of interfering with isoprenylation of RAS proteins by farnesyltransferase inhibitors (FTIs), has been proposed. Clinical phase II studies with the oral FTIs tipifarnib and lonafarnib in previously untreated AML, MDS and chronic myelomonocytic leukaemia yielded rather encouraging results while results in relapsed and/or refractory AML were disappointing. Results of a phase III trial in untreated AML in the elderly with tipifarnib were also disappointing. Clinical responses were not related to RAS mutations, suggesting additional actions of FTIs on other molecular targets. The combination of existing FTIs with other treatments, such as chemotherapy (in AML) and hypomethylating agents (in MDS and AML), is under investigation. Ongoing studies will also determine if gene profiling analysis may help to identify patients that will respond to FTIs.
 ...
PMID:Farnesyltransferase inhibitors and their potential role in therapy for myelodysplastic syndromes and acute myeloid leukaemia. 1841 Apr 57

Increased understanding of the cellular mechanisms associated with various malignancies has allowed researchers to develop agents that selectively target the cellular proteins and pathways implicated in the pathogenesis of malignancy. Tipifarnib is a specific and potent farnesyltransferase inhibitor that demonstrates in vivo and in vitro activity against a variety of human cancers. Although tipifarnib was initially thought to target the Ras protein, recent evidence suggests that the presence of ras mutations is not necessary for the antitumor effects of tipifarnib, and that tipifarnib may exert its effects downstream of Ras. The oral administration and favorable toxicity profile of tipifarnib, combined with its activity in a variety of intracellular pathways that have been implicated in the pathogenesis of hematologic malignancies, make it an especially attractive agent for use in patients with acute myeloid leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia (CML), and multiple myeloma. Because hematologic malignancies are likely driven by multiple genetic aberrations, the most effective treatment strategy will likely combine multiple agents with complementary mechanisms of action. Thus, additional studies of combination regimens that incorporate tipifarnib with other antineoplastic agents are crucial. Early results from studies combining tipifarnib with imatinib or etoposide in CML and AML have been promising and warrant further evaluation in larger clinical trials.
 ...
PMID:Farnesyltransferase inhibition in hematologic malignancies: the clinical experience with tipifarnib. 1849 98

Acute myeloid leukemia (AML) is the most common childhood malignancy. AML has therapeutically been difficult to treat. In 2001, the World Health Organization (WHO), in conjunction with the Society for Hematopathology and the European Association of Hematopathology, published a new classification for myeloid neoplasms. A number of chromosomal abnormalities are used to predict outcome and stratify therapeutic risk groups in children with AML. Recently, alterations in receptor tyrosine kinases, tyrosine phosphatases and in oncogenes such as RAS have been implicated in the pathogenesis of AML. This article aims to review the recent development in diagnosis, treatment and monitoring of AML. Better understanding of the molecular pathogenesis of AML has led to the development of target-specific therapies. Some of the new classes of drugs include monoclonal antibody directed against the CD33 antigen, farnesyltransferase inhibitors (FTI), and FMSlike tyrosine kinase 3 (FLT3) inhibitors. The role of allogenic SCT, particularly whether it should be done during first CR or reserved for second remission, remains the most controversial issue in pediatric AML. There is a need of collaboration with international pediatric cooperative oncology groups and definitive clinical trials in order to establish use of these newer molecules in pediatric populations.
 ...
PMID:Recent advances in management of acute myeloid leukemia (AML). 1876 95

Acute myeloid leukemia (AML) accounts for approximately 80% of acute leukemias diagnosed in adults. The elderly are disproportionately affected by AML, as 35% of newly diagnosed patients are aged >or=75 and the median age at diagnosis is 67. Elderly individuals also respond less well to standard chemotherapy than do younger individuals, as reflected by lower complete remission and relapse-free survival rates in major clinical trials. A higher prevalence of comorbid conditions as well as the unique biological features of elderly AML patients account for the relatively poor response to therapy observed in this population. Compared with AML in younger individuals, for example, AML in the elderly more often emerges from a preceding myelodysplastic syndrome and is more frequently associated with poor-prognosis karyotypes such as 5q- or 7q-. The introduction of novel therapies over the past decade has already altered the treatment paradigm of elderly individuals with AML. The first of these to emerge was gemtuzumab ozogamicin. Other agents are currently under evaluation in clinical trials, including inhibitors of multidrug resistance, farnesyltransferase inhibitors, novel nucleoside analogues, and inhibitors of the FMS-like tyrosine kinase-3. This review describes the biological features of AML in the elderly and summarizes both the current and emerging strategies for the treatment of this disease in older individuals.
 ...
PMID:Current and emerging strategies for the management of acute myeloid leukemia in the elderly. 1892 30

Acute myeloid leukemia (AML) is more prevalent in older adults, with an incidence in the United States of 17.6 per 100,000 for those 65 years of age, compared with an incidence of 1.8 per 100,000 for those <65 years of age. While there have been improvements in survival during the last decade for younger patients, prognosis in elderly patients is still poor; approximately 50% achieve complete responses, but many of them relapse. With increasing age, more patients are suboptimal candidates for standard induction chemotherapy due to poor performance status, pre-existing myelodysplasia, unfavorable cytogenetics, treatment-related AML, multidrug resistance protein expression, and CD34 positivity, which are often characteristic of this patient population. In addition, the presence of comorbid conditions make many treatment options less tolerable for elderly patients. Several investigators have described subgroups showing no benefit after intensive treatment approaches in recent years. However, several novel agents have been developed to treat elderly AML patients. These include new chemotherapeutic agents, such as nucleoside analogs, as well as targeted therapies like farnesyltransferase inhibitors, tyrosine kinase inhibitors, epigenetic drugs, and antibodies. On the other hand new insights into the biology of the disease lead to a better understanding of its heterogeneity. Thus, with a variety of novel substances at hand it is increasingly important to introduce a risk-adapted approach for the optimal management of patients. This review will identify subgroups not likely to benefit from intensive chemotherapy and highlight the efficacy and tolerability of new agents in the treatment of AML.
 ...
PMID:Emerging treatment strategies for acute myeloid leukemia (AML) in the elderly. 1895 21

The farnesyltransferase inhibitor tipifarnib exhibits modest activity against acute myelogenous leukemia. To build on these results, we examined the effect of combining tipifarnib with other agents. Tipifarnib inhibited signaling downstream of the farnesylated small G protein Rheb and synergistically enhanced etoposide-induced antiproliferative effects in lymphohematopoietic cell lines and acute myelogenous leukemia isolates. We subsequently conducted a phase 1 trial of tipifarnib plus etoposide in adults over 70 years of age who were not candidates for conventional therapy. A total of 84 patients (median age, 77 years) received 224 cycles of oral tipifarnib (300-600 mg twice daily for 14 or 21 days) plus oral etoposide (100-200 mg daily on days 1-3 and 8-10). Dose-limiting toxicities occurred with 21-day tipifarnib. Complete remissions were achieved in 16 of 54 (30%) receiving 14-day tipifarnib versus 5 of 30 (17%) receiving 21-day tipifarnib. Complete remissions occurred in 50% of two 14-day tipifarnib cohorts: 3A (tipifarnib 600, etoposide 100) and 8A (tipifarnib 400, etoposide 200). In vivo, tipifarnib plus etoposide decreased ribosomal S6 protein phosphorylation and increased histone H2AX phosphorylation and apoptosis. Tipifarnib plus etoposide is a promising orally bioavailable regimen that warrants further evaluation in elderly adults who are not candidates for conventional induction chemotherapy. These clinical studies are registered at www.clinicaltrials.gov as #NCT00112853.
 ...
PMID:Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia: a preclinical and phase 1 trial of the farnesyltransferase inhibitor tipifarnib (R115777, Zarnestra) combined with etoposide. 1944 68


<< Previous 1 2 3 4 5 Next >>