Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tyrosine kinase inhibitor (TKI) imatinb has radically changed the treatment of chronic myeloid leukemia (CML). Most patients treated in chronic phase can be expected to achieve a complete cytogenetic remission (CCyR). However, primary imatinib therapy fails in a number of patients initially, or relapse occurs later after a good cytogenetic response. Treatment of accelerated phase and blast crisis yields disappointing results and is rarely associated with long-term disease control. Imatinib failures can now be potentially salvaged with new TKIs or, if a donor exists, by a hematopoetic stem cell transplantation. Given these multiple effective treatment options, tight monitoring of cytogenetic and molecular response is essential in deciding when imatinib therapy should be abandoned for alternative therapy. This review will define the types of tests used to monitor the disease, provide clinically relevant endpoints, and outline guidelines for monitoring patients with CML on imatinib therapy.
Clin Lymphoma Myeloma 2008 Mar
PMID:Optimizing timing of secondary tyrosine kinase therapy in chronic myeloid leukemia. 1925 86

Imatinib is one of the most potent cancer therapeutic agents identified to date. Before the introduction of this tyrosine kinase inhibitor (TKI), 5-year survival in chronic myeloid leukemia (CML) was approximately 40%-60%, but since the introduction of imatinib, overall survival has increased to approximately 90% for patients with chronic-phase disease. However, nearly one fifth of patients are intolerant or resistant to imatinib, resulting in patients with persistent or progressive disease. Recent research has identified a number of additional compounds that more efficiently inhibit the Abl tyrosine kinase and additional kinases that potentially play a role in imatinib resistance. The advent of dasatinib and nilotinib has provided additional options for patients with progressive disease. A number of phase II clinical trials have recently demonstrated that these second-generation TKIs are well tolerated and effective in patients with Philadelphia chromosome-positive (Ph+) leukemias. Recent clinical trial developments raise questions regarding the proper dosage and schedule of these newer agents as well as the timing of their use in the treatment of patients with CML. Additionally, the development of nonoverlapping resistance patterns with sequential drug exposure argues for the possibility of a drug selection scheme that might limit the development of resistant disease. As the era of personalized medicine has begun to take shape in the 21st century, the addition of newer TKIs might facilitate this trend in the treatment of Ph+ leukemias.
Clin Lymphoma Myeloma 2008 Mar
PMID:Efficacy of various doses and schedules of second-generation tyrosine kinase inhibitors. 1925 87

Vandetanib is a novel, orally available inhibitor of different intracellular signaling pathways involved in tumor growth, progression, and angiogenesis: vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and REarranged during Transfection tyrosine kinase activity. Phase I clinical trials have shown that vandetanib is well tolerated as a single agent at daily doses < or =300 mg. In the phase II setting, negative results were observed with vandetanib in small cell lung cancer, metastatic breast cancer, and multiple myeloma. In contrast, three randomized phase II studies showed that vandetanib prolonged the progression-free survival (PFS) time of patients with non-small cell lung cancer (NSCLC) as a single agent when compared with gefitinib or when added to chemotherapy. Rash, diarrhea, hypertension, fatigue, and asymptomatic QTc prolongation were the most common adverse events. Antitumor activity was also observed in medullary thyroid cancer. Four randomized phase III clinical trials in NSCLC are exploring the efficacy of vandetanib in combination with docetaxel, the Zactima in cOmbination with Docetaxel In non-small cell lung Cancer (ZODIAC) trial, or with pemetrexed, the Zactima Efficacy with Alimta in Lung cancer (ZEAL) trial, or as a single agent, the Zactima Efficacy when Studied versus Tarceva (ZEST) and the Zactima Efficacy trial for NSCLC Patients with History of EGFR-TKI chemo-Resistance (ZEPHYR) trials. Based on a press release by the sponsor of these trials, the PFS time was longer with vandetanib in the ZODIAC and ZEAL trials; the ZEST trial was negative for its primary superiority analysis, but was successful according to a preplanned noninferiority analysis of PFS. Ongoing phase II and III clinical trials will better define the appropriate schedule, the optimal setting of evaluation, and the safety of long-term use of vandetanib.
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PMID:Vandetanib (ZD6474), a dual inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) tyrosine kinases: current status and future directions. 1934 11

Cytogenetic response (CyR), especially complete CyR (CCyR), has historically and is currently associated with a significant survival advantage in patients with chronic-phase chronic myeloid leukemia (CP-CML). CCyR represents a critical level of disease reduction irrespective of treatment type, and timely achievement demonstrates treatment-sensitive disease. Guidelines from European LeukemiaNet and the National Comprehensive Cancer Network therefore state that alternative therapies should be considered for patients not achieving CCyR by 6 or 12 months. Data from clinical trials indicate that early CCyR affords the best benefit:risk ratio by minimizing the mounting risk of disease progression, and the duration of CCyR when achieved affects disease progression. Treatment options for patients who fail to achieve CCyR on standard-dose imatinib (400 mg/day) include imatinib dose escalation, dasatinib, nilotinib, stem-cell transplantation, or a clinical trial. While molecular testing gauges further risk reduction, disease stability, and often elimination of BCR-ABL transcripts below detection threshold, CCyR remains the most important surrogate for long-term survival and cytogenetic testing remains a key part of patient care in the management of CML, particularly early in response. Longerterm follow-up data will be required to confirm CCyR as a surrogate marker for survival in imatinib-resistant patients treated with the secondgeneration tyrosine kinase inhibitors, dasatinib and nilotinib.
Clin Lymphoma Myeloma 2009 Jun
PMID:Response dynamics in chronic-phase chronic myeloid leukemia. 1952 90

The identification of proliferation/survival pathways constitutively activated by genetic alterations in multiple myeloma (MM), or sustained by the bone marrow (BM) microenvironment, provides novel opportunities for the development of targeted therapies. The deregulated function of protein tyrosine kinases plays a critical role in driving MM malignant phenotype. We investigated the effects of the multi-target tyrosine kinase inhibitor RPI-1 in a panel of human MM cell lines, including t(4;14) positive cell lines expressing the TK receptor FGF-R3. Cells harboring FGF-R3 activating mutations (KMS11 and OPM2) displayed the highest sensitivity to RPI-1 antiproliferative effect. The stimulating effect of the aFGF ligand was abrogated in cells harboring a non-constitutively active receptor. Drug treatment inhibited activation and expression of the FGF-R3(Y373C) mutant as well as aFGF-dependent signaling involving AKT and ERKs. Inhibition of JAK2, an additional RPI-1 target, resulted in STAT3 inactivation. Blockade of these proliferation/survival pathways was associated with caspase-dependent apoptosis. Moreover, drug treatment abrogated proliferative and pro-invasive stimuli provided by conditioned medium from mesenchymal stromal cells. Gene expression profile of KMS11 cells showed 22 upregulated and 52 downregulated genes upon RPI-1 treatment, with an early modulation of genes implicated in MM pathobiology such as SAT-1, MYC, MIP-1alpha/beta, FGF-R3, and the growth factor receptor B-cell maturation antigen (BCMA). Thus, concomitant blockade of FGF-R3 and JAK2 results in inhibition of several MM-promoting pathways, including BCMA-regulated signaling, and downregulation of disease-associated proteins. These data may have therapeutic implications in the design of treatment strategies resulting in the concomitant inhibition of FGF-R3 and JAK2 signaling pathways in t(4;14) MM.
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PMID:Concomitant downregulation of proliferation/survival pathways dependent on FGF-R3, JAK2 and BCMA in human multiple myeloma cells by multi-kinase targeting. 1955 70

Serenoa repens, a palm species native to the Southeastern United States, is one of the widely used phytotherapeutic agents in benign prostatic hyperplasia. In this study, we found for the first time that Serenoa repens induced growth arrest of a variety of human leukemia cells including U266 and RPMI 8226 multiple myeloma cells as measured by mitochondrial-dependent conversion of the 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay. TUNEL assays showed that Serenoa repens induced apoptosis of U266 cells in a time- and dose-dependent manner. Serenoa repens also increased the expression of cleaved-PARP or p27 protein in different human leukemia cell lines. In addition, we found that Serenoa repens down-regulated basal level of phosphorylated form of signal transducer and activator of transcription 3 (STAT 3) and Interleukin-6 induced level of phosphorylated form of STAT 3 and extracellular signal-related kinase (ERK) were also reduced after Serenoa repens treatment in U266 cells. Furthermore, we found that inhibition of STAT 3 signaling by Serenoa repens or Janus family of tyrosine kinase (JAK) inhibitor of AG490 enhanced the ability of docetaxel to inhibit the growth of U266 and RPMI 8226 cells, as measured by trypan blue exclusion test. These results indicate that Serenoa repens might be useful for the treatment of individuals with multiple myeloma.
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PMID:Serenoa repens induces growth arrest and apoptosis of human multiple myeloma cells via inactivation of STAT 3 signaling. 1957 80

Although most children with acute lymphoblastic leukemia (ALL) are cured, certain subsets have a high risk of relapse. Relapse risk can be predicted by early response to therapy, clinical and pharmacogenetic features of the host, and genetic characteristics of leukemic cells. Though early treatment response can be assessed by the peripheral blast cell count after 1 week of single-agent glucocorticoid treatment or percent of bone marrow blasts by morphology after 1 or 2 weeks of multiagent induction treatment, determination of minimal residual disease by polymerase chain reaction (PCR) or flow cytometry after 2 to 6 weeks of induction is the most precise and useful measure. Augmented therapy has improved outcome for the poor responders to initial treatment. Infants with mixed-lineage leukemia (MLL)-rearranged ALL comprise a very poor-risk group wherein further intensification of chemotherapy causes significant toxicity. Hybrid protocols incorporating drugs effective for acute myeloid leukemia could improve survival, a strategy being tested in international trials. Studies on the biology of MLL-induced leukemogenesis have prompted the development of novel targeted agents, currently under evaluation in clinical trials. Short-term outcomes of patients with Philadelphia chromosome (Ph)-positive ALL have improved significantly by adding tyrosine kinase inhibitors to standard chemotherapy regimens. New agents and methods to overcome resistance are under investigation, and allogeneic stem cell transplantation is recommended for certain subsets of patients, for example those with Ph+ and T-cell ALL with poor early response. Genome-wide interrogation of leukemic cell genetic abnormalities and germline genetic variations promise to identify new molecular targets for therapy.
Clin Lymphoma Myeloma 2009
PMID:High-risk childhood acute lymphoblastic leukemia. 1977 45

Allogeneic stem cell transplantation (ASCT) is a potentially curative treatment for patients with chronic myelogenous leukemia (CML) and was previously considered the preferred treatment for newly diagnosed CML. The success of imatinib has changed treatment recommendations, and allogeneic transplants are now reserved for imatinib treatment failures. Previous imatinib treatment does not compromise the results of ASCT, but patients with overt transformed disease have poor results. It is unclear whether patients whose disease is considered to have failed imatinib should be referred immediately for ASCT or receive treatment with a second-generation tyrosine kinase inhibitors (TKI). Patients whose disease fails 2 TKIs should receive ASCT if possible. Nonmyeloablative preparative regimens reduce the toxicity and treatment-related mortality associated with the transplantation procedure and allow transplantations to be performed in older and medically infirm patients. This approach, including posttransplantation treatment with TKIs and donor lymphocyte infusion, produces a high fraction of durable molecular complete remissions.
Clin Lymphoma Myeloma 2009
PMID:Nonmyeloablative allogeneic stem cell transplantation for chronic myelogenous leukemia in the imatinib era. 1977 50

The outlook for newly diagnosed patients with chronic myeloid leukemia (CML) in the imatinib era is excellent for most patients. However, imatinib failure is observed in around 25%-30% of patients. With the availability of second-line tyrosine kinase inhibitor therapy and/or allogeneic transplantation, many of these patients with imatinib failure can still achieve durable cytogenetic and molecular responses. Early evidence of imatinib resistance, when the biology of the emerging leukemia might still be relatively favorable, is the best time to switch to second-line therapy. Close cytogenetic and molecular monitoring will facilitate early intervention in appropriate cases. However, caution should be used when interpreting minimal residual disease data, and the danger of inappropriate changes in therapy based on assay fluctuations should be recognized. A significant increase in the level of BCR-ABL to a level > 0.1% on the international scale (major molecular response) should prompt a repeat BCR-ABL assay, a mutation screen, and possibly marrow cytogenetics. What constitutes a significant increase depends on the laboratory-specific measurement reliability. The possibilities of poor compliance or drug interactions should be considered. If the repeat BCR-ABL assay, fluorescence in situ hybridization assay, or cytogenetics confirms loss of complete cytogenetic response or if a mutation is identified, a dose increase or a switch in therapy to a second-line kinase inhibitor might be indicated. At least until complete molecular response is achieved, regular real-time polymerase chain reaction monitoring reinforces the fact that leukemia is still present and that compliance is a challenge that requires ongoing vigilance from the patient and the clinician.
Clin Lymphoma Myeloma 2009
PMID:Measuring minimal residual disease in chronic myeloid leukemia: fluorescence in situ hybridization and polymerase chain reaction. 1977 51

Chronic myeloid leukemia (CML) is characterized at the molecular level by the presence of the Philadelphia chromosome (Ph) and the resultant oncogenic signaling by the BCR-ABL fusion protein. The treatment and outlook for CML were revolutionized by the introduction of imatinib, but resistance is a substantial barrier to successful treatment in many patients. Introduction of the second-generation tyrosine kinase inhibitors (TKI) dasatinib and nilotinib has provided effective therapeutic options for many patients with resistance to front-line imatinib. However, the T315I mutation remains a significant clinical issue because it is insensitive to all currently available agents. A number of new agents are in development and many hold the promise of activity in T315I-mutated disease. Successful treatment of patients with disease harboring T315I might lie in the effective combination or sequencing of these new agents with existing TKI therapies.
Clin Lymphoma Myeloma 2009
PMID:Second-line therapy and beyond resistance for the treatment of patients with chronic myeloid leukemia post imatinib failure. 1977 52


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