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)

Chronic myeloid leukemia (CML) is a progressive and often fatal myeloproliferative disorder. The hallmark of CML is an acquired chromosomal translocation known as the Philadelphia chromosome (Ph) that results in the synthesis of the BCR-ABL fusion protein, a constitutively active tyrosine kinase (TK). The introduction of imatinib, a TK inhibitor (TKI) specific for BCR-ABL, was a major breakthrough in CML therapy. Although most patients respond to first-line imatinib therapy, some experience a loss of response (resistance) or require treatment discontinuation because of toxicity (intolerance). In patients for whom standard-dose imatinib therapy (400 mg/day) fails, imatinib dose escalation (600-800 mg/day) is a second-line option. However, high-dose imatinib is not an appropriate approach for patients experiencing drug toxicity, and there remain questions over the durability of responses achieved with this strategy. Alternative second-line options include the newer TKIs dasatinib and nilotinib. A substantial amount of long-term data for these agents is available. Although both are potent and specific BCR-ABL TKIs, dasatinib and nilotinib exhibit unique pharmacologic profiles and response patterns relative to different patient characteristics, such as disease stage and BCR-ABL mutational status. To optimize therapeutic benefit, clinicians should select treatment based on each patient's historical response, adverse event tolerance level, and risk factors.
Clin Lymphoma Myeloma Leuk 2010 Jun
PMID:Clinical algorithms for the treatment of patients with chronic myeloid leukemia: the 2010 perspective. 2052 8

Molecular target therapy is progressive and promising in various hematological malignancies. Imatinib is now the treatment of choice for chronic-phase chronic myeloid leukemia. Eight-year data from the pivotal trial of imatinib, the IRIS trial, showed high long-term response rates and favorable tolerability profile compared with previous therapies. For patients with primary resistance to imatinib, hematologic disease recurrence, or emergent BCR-ABL kinase domain mutations, the potent second generation tyrosine kinase inhibitors dasatinib and nilotinib are now available. Since the introduction of all-trans retinoic acid (ATRA) in the 1980s, the strategy for treating acute promyelocytic leukemia (APL) has shifted from conventional chemotherapy to cell differentiation. The combination of ATRA and anthracycline-based chemotherapy is currently the standard approach to treat newly-diagnosed APL. Multiple myeloma (MM) is also one of the major therapeutic targets in using molecular based technology. The recent availability of clinical data regarding thalidomide and lenalidomide has provided effective treatment options for patients with both newly diagnosed and relapsed/refractory MM. Overall, this paper focuses on a comprehensive review of the current literature and provides data supporting molecular target therapy for patients with CML, APL, or MM.
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PMID:[Oral molecular targeting agents in hematological malignancy]. 2064 1

Authors have reviewed literature about the management of patients with cardiologic disease occurring secondary to hematologic pathology itself or its therapy, with a focus on infiltration of myocardium in acute and chronic leukemia, lymphoma, multiple myeloma, and hypereosinophilic syndrome. Moreover, they evaluated chemotherapy-associated toxicity, particularly for new drugs such as monoclonal antibody therapy, tyrosine kinase inhibitors, arsenic trioxide, bortezomib, and epigenetic therapy. In fact, cardiac toxicity may range from asymptomatic subclinical abnormalities, such as electrocardiographic changes and left ventricular ejection decline, to life-threatening events and lead to chemotherapy dose reduction and delay and, in some cases, for patients with severe side effects, discontinuation of treatment. Finally, they discussed on the identification of early markers of cardiac injury and on cardiac stem cell therapy as a promising approach to facilitate myocardial regeneration.
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PMID:Cardiac involvement in patients with hematologic malignancies. 2068 45

Imatinib, a tyrosine kinase inhibitor, is the first-line therapy for chronic myeloid leukemia (CML). The majority of patients continue treatment for their lifespan because discontinuation generally results in relapse. Many patients treated with imatinib experience adverse events (AEs) at some time during their treatment. Commonly encountered AEs and their management are well known. However, in addition to the common AEs with imatinib, there is a significant number of patients who display either uncommon or delayed AEs. These events can involve cardiac, renal, or dermatologic problems, and fluid retention. Herein, we review these less-than-common side effects and the hazard of administering imatinib during pregnancy. While chronic treatment with imatinib has revolutionized CML prognosis, physicians should be aware of both the common and uncommon adverse reactions.
Clin Lymphoma Myeloma Leuk 2010 Oct
PMID:Uncommon or delayed adverse events associated with imatinib treatment for chronic myeloid leukemia. 2103 Mar 45

A concept that currently steers the development of cancer therapies has been that agents directed against specific proteins that facilitate tumorigenesis or maintain a malignant phenotype will have greater efficacy, less toxicity and a more sustained response relative to traditional cytotoxic chemotherapeutic agents. The clinical success of the targeted agent Imatinib mesylate as an inhibitor of the tyrosine kinase associated with the breakpoint cluster region-Abelson oncogene locus (BCR-ABL) in the treatment of Philadelphia-positive chronic myelogenous leukemia (CML) has served as a paradigm. While intellectually gratifying, the selective targeting of a single driver event by a small molecule, e.g., kinase inhibitor, to dampen a tumor-promoting pathway in the treatment of solid tumors is limited by many factors. Focus can alternatively be placed on targeting fundamental cellular processes that regulate multiple events, e.g., protein degradation, through the Ubiquitin (Ub)+Proteasome System (UPS). The UPS plays a critical role in modulating numerous cellular proteins to regulate cellular processes such as signal transduction, growth, proliferation, differentiation and apoptosis. Clinical success with the proteasome inhibitor bortezomib revolutionized treatment of B-cell lineage malignancies such as Multiple Myeloma (MM). However, many patients harbor primary resistance and do not respond to bortezomib and those that do respond inevitably develop resistance (secondary resistance). The lack of clinical efficacy of proteasome inhibitors in the treatment of solid tumors may be linked mechanistically to the resistance detected during treatment of hematologic malignancies. Potential mechanisms of resistance and means to improve the response to proteasome inhibitors in solid tumors are discussed.
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PMID:The ubiquitin+proteasome protein degradation pathway as a therapeutic strategy in the treatment of solid tumor malignancies. 2135 40

The coexistence of lung cancer and multiple myeloma (MM) is rare. A search of the English literature revealed only 5 case reports to date. We describe a case of MM that presented in a 78-year-old lung cancer patient after 20 months of treatment with gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor. We also review previously reported cases of concurrent development of lung cancer and MM.
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PMID:Multiple myeloma emerging after prolonged gefitinib treatment for non-small cell lung carcinoma. 2151 69

Before the introduction of tyrosine kinase inhibitors, the prognosis for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia was poor. The treatment of choice, stem cell transplantation, is a potentially curative option, but it is available only for a minority of patients and is associated with significant risk of morbidity and mortality. Although imatinib is largely effective, a substantial proportion of patients become resistant or intolerant to it. The activity of imatinib may be enhanced by coadministration with chemotherapy; such treatment is effective in many patients. Dasatinib is established as a second-line treatment in patients with resistance to or intolerance of imatinib. Recent data suggest that dasatinib, either alone or in combination with chemotherapy, has utility as first-line therapy. Dasatinib is more potent than imatinib, is less susceptible to drug-resistance mechanisms, and has been shown to penetrate the blood-brain barrier, making it potentially effective for treating central nervous system disease. Patients who relapse during treatment with dasatinib frequently carry the T315I mutation of BCR-ABL. Future regimens combining dasatinib with an agent able to inhibit this mutation may further improve outcome.
Clin Lymphoma Myeloma Leuk 2011 Apr
PMID:Managing Philadelphia chromosome-positive acute lymphoblastic leukemia: role of tyrosine kinase inhibitors. 2157 24

The introduction of imatinib in the treatment of chronic myeloid leukemia (CML) represents the most successful example of targeted therapy in human cancer. However, leukemic stem cells are insensitive to tyrosine kinase inhibitors (TKIs) and contribute to the persistence of disease by representing a reservoir of selfrenewing cells that replenish the disease after drug discontinuation. This finding has refocused the interest of scientists toward drug combinations, ie, treating with TKIs and simultaneously targeting alternative survival mechanisms. One candidate target mechanism is autophagy, a cellular recycling process that acts as a cytoprotective shield in CML cells in response to TKI-induced stress and in other cancer cells surviving in an inhospitable microenvironment. On that basis, inhibition of autophagy has now become an exciting option for combination treatment in cancer, and clinical trials have been initiated in solid and hemopoietic tumors such as CML, chronic lymphocytic leukemia, and multiple myeloma. This review describes the biology of CML and elucidates how the molecular driver BCR-ABL led to the development of TKIs. We then discuss the molecular regulation of autophagy and the potential for autophagy inhibition as the next step in our attempt to tackle the problem of CML persistence to offer a curative option.
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PMID:Kill one bird with two stones: potential efficacy of BCR-ABL and autophagy inhibition in CML. 2169 57

Despite the advantage observed with novel drugs such as bortezomib, thalidomide, or lenalidomide, multiple myeloma (MM) remains incurable and there is a clear need for new drugs or combinations based on the pathogenetic mechanism of MM. One of the proposed mechanisms in MM pathogenesis is the involvement of kinase molecules in the growth and survival of myelomatous cells. In this study, we have explored the optimal combination for dasatinib, a tyrosine kinase inhibitor, in MM cells. A clear synergistic effect was observed with the triple combination of dasatinib with bortezomib and dexamethasone which was evident even in the presence of bone marrow microenvironment. Experiments performed on freshly isolated patients' cells also demonstrated potentiation of response in the triple as compared with the agents alone or in double combinations. Gene expression profiling experiments provided some clues on the transcriptional rationale underlying this potentiation, as the triple combination led to significant deregulation of genes involved in cell death, cell growth, proliferation, DNA replication, repair and recombination, and cell-cell signaling. Some of these results were further confirmed by apoptosis and cell cycle experiments and also by Western blot and PCR. These data provide the rationale for the use of this novel combination in MM patients.
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PMID:Transcriptomic rationale for the synergy observed with dasatinib + bortezomib + dexamethasone in multiple myeloma. 2172 Jul 45

The success of tyrosine kinase inhibition of the BCR-ABL fusion gene with imatinib in the treatment of chronic myeloid leukemia (CML) has resulted in the use of molecular detection techniques for routine clinical management. Current clinical guidelines recommend the use of molecular testing of BCR-ABL transcript levels by quantitative real-time transcriptase polymerase chain reaction (qRT-PCR) every 3 to 6 months. However, qRT-PCR methods have not yet been standardized, particularly in the United States, where most patients are initially treated outside of academic practices. The lack of standard methods for molecular monitoring has resulted in the failure to follow National Comprehensive Cancer Network and European LeukemiaNet guideline recommendations and in the misinterpretation of test results. Standardization of molecular monitoring methods and adherence to guideline recommendations are important for optimal patient management. In this article, we provide an update on the current clinical trial results by using the molecular technique to monitor patient response. Current problems and efforts in standardizing the qRT-PCR technique and reporting are reviewed. We provide examples of potential problems of various reference laboratory reports and present recommendations for assessing molecular test results. These recommendations seem particularly important because nilotinib and dasatinib appear to have improved the molecular response in the initial treatment of CML.
Clin Lymphoma Myeloma Leuk 2011 Oct
PMID:Translating trial-based molecular monitoring into clinical practice: importance of international standards and practical considerations for community practitioners. 2172 5


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