Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Success of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) has given patients hope for a long disease-free-survival. A longer survival raises the question of late effects, including development of another malignancy. Records of 1445 patients with CML/myeloproliferative neoplasm or other hematologic malignancies treated with TKIs were reviewed to investigate frequency and characteristics of second malignancies (other than acute myeloid leukemia, acute lymphocytic leukemia, or myelodysplastic syndrome). The number of second cancers was compared with the number expected from the Surveillance, Epidemiology, and End Results database. After a median follow-up of 107 months (range, 13-362 months) after CML/myeloproliferative neoplasm diagnosis, 66 patients (4.6%) developed 80 second cancers, including skin (31%), prostate (15%), melanoma (13%), digestive system (10%), kidney (4%), thyroid (4%), breast (3%), chronic lymphocytic leukemia (3%), hepatobiliary (3%), and other cancers (14%). Excluding nonmelanoma skin cancers, 55 second cancers were seen in 51 (3.5%) of all patients treated. The risk of second cancer was lower than expected (observed-to-expected ratio, 0.6; 95% confidence interval, 0.44-0.81). Second cancers occur in a small percentage of patients receiving therapy with TKIs for hematologic malignancies, mostly CML. No evidence at the moment suggests that exposure to TKIs increases the risk of developing second cancers.
 ...
PMID:Malignancies occurring during therapy with tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) and other hematologic malignancies. 2184 2

We aimed to determine the prognostic impact of monosomal karyotype (MK) in acute myeloid leukemia (AML) in the context of the current World Health Organization (WHO) classification and to evaluate the outcome of MK(+) patients after allogeneic HSCT. Of 1058 patients with abnormal cytogenetics, 319 (30%) were MK MK(+). MK(+) patients were significantly older (P = .0001), had lower white blood counts (P = .0006), and lower percentages of BM blasts (P = .0004); MK was associated with the presence of -5/5q-, -7, 7q-, abnl(12p), abnl(17p), -18/18q-, -20/20q-, inv(3)/t(3;3), complex karyotype (CK), and myelodysplasia (MDS)-related cytogenetic abnormalities (P < .0001, each); and NPM1 mutations (P < .0001), FLT3 internal tandem duplications (P < .0001), and tyrosine kinase domain mutations (P = .02) were less frequent in MK(+). Response to induction therapy and overall survival in MK(+) patients were dismal with a complete remission rate of 32.5% and a 4-year survival of 9%. MK retained its prognostic impact in AML with CK, AML with MDS-related cytogenetic abnormalities, and in a revised definition (MK-R) excluding cases with recurrent genetic abnormalities according to WHO classification and those with derivative chromosomes not leading to true monosomies. In younger patients, allogeneic HSCT from matched related and unrelated donors resulted in a limited improvement of overall survival.
 ...
PMID:Monosomal karyotype in adult acute myeloid leukemia: prognostic impact and outcome after different treatment strategies. 2209 50

Constitutive activation of FLT3 by internal tandem duplication (ITD) is one of the most common molecular alterations in acute myeloid leukemia (AML). FLT3/ITD mutations have also been observed in myelodysplastic syndrome patients both before and during progression to AML. Previous work has shown that insertion of an FLT3/ITD mutation into the murine Flt3 gene induces a myeloproliferative neoplasm, but not progression to acute leukemia, suggesting that additional cooperating events are required. We therefore combined the FLT3/ITD mutation with a model of myelodysplastic syndrome involving transgenic expression of the Nup98-HoxD13 (NHD13) fusion gene. Mice expressing both the FLT3/ITD and NHD13 transgene developed AML with 100% penetrance and short latency. These leukemias were driven by mutant FLT3 expression and were susceptible to treatment with FLT3 tyrosine kinase inhibitors. We also observed a spontaneous loss of the wild-type Flt3 allele in these AMLs, further modeling the loss of the heterozygosity phenomenon that is seen in human AML with FLT3-activating mutations. Because resistance to FLT3 inhibitors remains an important clinical issue, this model may help identify new molecular targets in collaborative signaling pathways.
 ...
PMID:Knock-in of a FLT3/ITD mutation cooperates with a NUP98-HOXD13 fusion to generate acute myeloid leukemia in a mouse model. 2232 52

Acute promyelocytic leukemia (APL) is a relatively common form of acute myeloid leukemia (AML) that has an excellent prognosis. In contrast, secondary acute myeloid leukemias, including therapy-related AML and AML with myelodysplasia-related changes, have a relatively poor prognosis. We identified 9 cases of APL at our institution in which there was a history of chemotherapy, radiotherapy, chronic immunosuppression, or antecedent myelodysplastic syndrome. The clinical and pathologic findings in these cases of secondary APL were compared with the clinical and pathologic findings in cases of de novo APL. We found that secondary and de novo APL had abnormal promyelocytes with similar morphologic and immunophenotypic features, comparable cytogenetic findings, comparable rates of FMS-like tyrosine kinase mutations, and similar rates of recurrent disease and death. These data suggest that secondary APL is similar to de novo APL and, thus, should be considered distinct from other secondary acute myeloid neoplasms.
 ...
PMID:Clinical and pathologic features of secondary acute promyelocytic leukemia. 2233 51

Myeloid sarcoma (MS) is a localized, extramedullary tumor of acute myeloid leukemia (AML) that typically presents either de novo or concomitantly with myeloproliferative neoplasms (MPN), AML and myelodysplastic syndrome. Patients who have MS must be treated with intensive chemotherapy, as are patients with AML, because MS usually progresses to a systemic manifestation and leads to dismal outcomes. FIP1L1-PDGFRA-associated MPN, a subtype of myeloid and lymphoid neoplasm, is characterized by eosinophilia and abnormalities in the PDGFRA, PDGFRB or FGFR1 gene. Fusion of the FIP1L1 and PDGFRA genes activates the tyrosine kinase. As a result, imatinib mesylate (IM) is widely used for the treatment of this disorder. The coexistence of FIP1L1-PDGFRA-associated MPN and MS is extremely rare. Patients with this condition fail to achieve durable remission and long-term survival without a combination of intensive chemotherapy and IM. Here, we report a case of MS and FIP1L1-PDGFRA-associated MPN that was successfully treated with IM monotherapy.
 ...
PMID:Complete response of myeloid sarcoma with FIP1L1-PDGFRA -associated myeloproliferative neoplasms to imatinib mesylate monotherapy. 2272 48

Lenalidomide (LEN) is an immunomodulatory drug (IMiD) which exerts tumoricidal effects and has immunomodulatory, anti-inflammatory and anti-angiogenic properties that synergistically keep the tumor in remission. It is currently approved as second-line therapy for multiple myeloma (MM) and for 5q defective myelodysplastic syndrome, while ongoing studies are at present evaluating its role in both solid and hematologic malignancies. Based on its high activity as an anti-myeloma drug with a good tolerability profile, LEN is currently gaining interest in both preclinical and clinical research for combinatory treatments with novel agents including monoclonal antibodies, immunotoxins, tyrosine kinase inhibitors, new proteasome inhibitors and epigenetic-interfering agents as well as with new compounds targeting the cancer stem cell niche. Preliminary data from clinical studies are encouraging and suggest a favorable safety profile, although the long-term tolerability of these combinatory regimens needs to be carefully evaluated since an increased incidence of new primary tumors associated with LEN treatment has recently been reported. Thus, from bench to bedside studies are required to design clinical trials for new drug combination approval.
 ...
PMID:Novel lenalidomide-based combinations for treatment of multiple myeloma. 2280 97

FMS-like tyrosine kinase III (FLT3) mutations occur in one-third of acute myeloid leukemia (AML) patients and predict poor outcome. The incidence and impact of FLT3 in myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) is unknown. We conducted a retrospective review to identify WHO MDS and CMML patients with FLT3 mutations at diagnosis. A total of 2,119 patients with MDS and 466 patients with CMML were evaluated at MD Anderson between 1997 and 2010. Of these, FLT3 mutation analysis was performed on 1,232 (58%) MDS and 302 (65%) CMML patients. FLT3 mutations were identified in 12 (0.95%) MDS patients: 9 (75%) had FLT3-ITD mutation and 3 had FLT3-tyrosine kinase domain (TKD) mutation. MDS patients with FLT3 mutations were younger (P = 0.02) and presented as RAEB (P = 0.03) more frequently. Median overall survival (OS) for FLT3-mutated MDS patients was 19.0 months versus 16.4 months for FLT3-nonmutated MDS patients (P = 0.08). FLT3 mutations were identified in 13 (4.3%) CMML patients: 8 had FLT3-ITD mutation and 5 had FLT3-TKD mutation. There were no significant differences in demographic and disease characteristics among CMML patients with and without FLT3 mutations. Median OS for FLT3-mutated CMML patients was 10.8 months versus 21.3 months for FLT3-nonmutated CMML patients (P = 0.12). FLT3 occurs in MDS and CMML at a lower frequency than AML and does not predict poor outcome.
 ...
PMID:FLT3 mutations in myelodysplastic syndrome and chronic myelomonocytic leukemia. 2311 6

Chronic myelomonocytic leukemia (CMML) is a clonal disorder sharing features of myelodysplastic syndromes and chronic myeloproliferative neoplasms. Although rare chromosomal aberrations and point mutations are reported in CMML, the molecular defects underlying CMML are largely unknown. ROS1 encodes a tyrosine kinase that is abnormally expressed and translocated in brain and lung cancers. In this study we show that ROS1 is abnormally activated in the CD34+ compartment of approximately 70% of CMML patients resulting in the activation of the Erk/Akt pathways through the Grb2/SOS complex thus revealing a central oncogenic role for ROS1 in CMML which might represent a molecular target.
 ...
PMID:Aberrant activation of ROS1 represents a new molecular defect in chronic myelomonocytic leukemia. 2341 11

The acquisition of secondary chromosomal aberrations in chronic myeloid leukemia (CML) patients with Philadelphia chromosome-positive (Ph+) karyotype signifies clonal evolution associated with the progression of the disease to its accelerated or blastic phase. Therefore, these aberrations have clinical and biological significance. T(3;12)(q26;p13), which is a recurrent chromosomal aberration observed in myeloid malignancies, is typically associated with dysplasia of megakaryocytes, multilineage involvement, short duration of any blastic phase, and extremely poor prognosis. We have identified a recurrent reciprocal translocation between chromosomes 3 and 12 with different breakpoint at bands 3q21 in the malignant cells from a 28-year-old man. The patient was initially diagnosed as having Ph+ CML in the chronic phase. The t(3;12)(q21;p13) translocation occurred 4 years after the patient was first diagnosed with CML while undergoing tyrosine kinase inhibitor therapy. We confirmed the t(3;12)(q21;p13) translocation via fluorescence in situ hybridization assay by using whole-chromosome paint probes for chromosomes 3 and 12. Our findings demonstrate that, similar to other recurrent translocations involving 3q26 such as t(3;3) and t(3;21), the t(3;12)(q21;p13) translocation is implicated not only in myelodysplastic syndrome and acute myeloid leukemia but also in the progression of CML. These findings extend the disease spectrum of this cytogenetic aberration.
 ...
PMID:A novel t(3;12)(q21;p13) translocation in a patient with accelerated chronic myeloid leukemia after imatinib and nilotinib therapy. 2369 45

The drugs used to treat hematologic disorders constitute an extraordinary array of agents and include therapy for anemias, bleeding diatheses, thromboembolism and hematologic malignancies. Within many of these categories, hematologic therapies represent molecular understanding of the disease pathophysiology and a treatment targeted precisely at the known aberration. In this chapter we discuss these treatments, with greater emphasis on the most commonly used agents and the latest advances in the specific field. The chapter includes discussion on old (cyclooxygenase inhibitors) and new antiplatelet agents (ADP receptor P2Y12 inhibitors), newly described oral thrombin inhibitors such as dabigatran, treatment targeted at the bcr-abl tyrosine kinase in chronic myeloid leukemia and demethylating agents in myelodysplasia. The discussion is also oriented towards neurologic implications, both therapeutic and toxic, for each therapy or therapeutic group.
...
PMID:Commonly used drugs in hematologic disorders. 2436 76


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>