Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Imatinib targets KIT and platelet-derived growth factor receptors (PDGFR) and is highly effective in the treatment of CML and GIST patients. Pancreatic cancers express KIT and PDGFRs. Therefore, 26 patients with unresectable pancreatic cancer were randomized to either gemcitabine (1000 mg/m2 weekly) or imatinib (2x400 mg po) treatment daily. Pancreatic adenocarcinoma was confirmed histologically and expression of KIT and PDGFRbeta was determined immunohistochemically in the biopsy specimens. Quality of life was assessed with two standard questionnaires. No objective responses were seen in either group. Median time to progression was 77 and 29 days (P=0.411) and median survival time was 140 and 60 days (P=0.517) for gemcitabine and imatinib, respectively. Survival and treatment responses were independent of KIT and PDGFRbeta expression in patients treated with imatinib. Grade 3/4 toxicities of imatinib treatment were anemia, elevated liver enzymes, vomiting, and dyspnea. Patients treated with imatinib reported diarrhoea and/or altered bowel function more frequently, which were treatable symptomatically. Quality of life was similar in both groups. In this small series of pancreatic cancer patients, treatment with imatinib was not associated with a significant control of cancer progression.
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PMID:The tyrosine kinase inhibitor imatinib fails to inhibit pancreatic cancer progression. 1589 16

Ferrets were used to demonstrate the potential of a killed whole cell vaccine prepared from Campylobacter jejuni to protect against disease. C. jejuni strain 81-176 was grown in BHI broth, formalin-fixed, and resuspended in PBS to a concentration of 10(10) cells per ml. This vaccine (CWC) or live organisms were delivered orally with a nasogastric tube into anesthetized animals treated to reduce gastric acidity and intestinal motility. When 5x10(10) CFU of the vaccine strain (Lior serotype 5) or one of two other serotypes, CGL-7 (Lior 4) or BT44 (Lior 9), was used to challenge the ferrets, all of the animals developed a mucoid diarrhea. If the animals had been challenged with 5x10(9) CFU of the homologous strain 1 month before challenge with 10(10) CFU, 80-100% protection against disease was seen. This protection was also obtained after an initial exposure to the 81-176 strain followed by challenge with either of the heterologous strains. CWC was used to see if protection demonstrated with the live organisms could be produced with the non-living preparation. When 10(9) cells of CWC was given as two doses 7 days apart with or without 25mug of a coadministered mucosal adjuvant, LT(R192G), only 40-60% of the animals were protected. If the regimen was changed to four doses given 48h apart, 80% of the animals were free of diarrhea after subsequent challenge. Increasing the number of cells in the four dose regimen to 10(10) cells did not improve protection. Animals given four doses of 10(10) cells combined with LT(R192G) were subsequently challenged with 10(10) cells of the homologous strain or the heterologous strain CGL-7. The CWC protected against both strains. Serum IgG antibody titers determined by ELISA showed little increase following the CWC four dose vaccination regimen, compared to animals given one dose of the live organism. On subsequent challenge, however, both CWC vaccinated and live-challenged ferrets showed comparable antibody titer increases above those obtained following the initial challenge or vaccination. Western blots were used to show that the immunodominant antigen in vaccinated animals was a 45kDa protein, while in ferrets challenged with live organisms the immunodominant antigen was a 62kDa protein. These data show that the CWC can be used to protect against disease caused by Campylobacter. They also show that protection and serum IgG responses do not depend upon the use of the mucosal adjuvant and that cross protection among some of the major serotypes of Campylobacter responsible for human disease is possible.
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PMID:Prevention of disease in ferrets fed an inactivated whole cell Campylobacter jejuni vaccine. 1600 42

We report the first case of Phialemonium obovatum fungemia with subsequent caseating granulomatas in the lung and Crohn disease-like involvement of the gastrointestinal tract in a bone marrow transplant recipient. This phaeoid fungus has been rarely described as an opportunistic infection in immunosuppressed patients. The patient was diagnosed with chronic myelogenous leukemia and underwent subsequent peripheral bone marrow transplant. After 6 months, he developed graft-versus-host disease of the skin and liver with fever and severe diarrhea. Fecal bacterial cultures and cytomegalovirus serologies were negative. Computed tomographic scan showed a peripheral pulmonary mass. A lung wedge biopsy of the lesion showed septate branching hyphae (4-5 microm in diameter) with terminal globular structures (10 microm in diameter). The hyphae were similar in width to that of an Aspergillus species but had a more moniliform appearance. Blood cultures grew a pure culture of P. obovatum. He was treated with amphotericin B and itraconazole for 6 months without remission of the diarrhea. Biopsies of the stomach, colon, and rectum showed granulomatous inflammation with marked crypt distortion simulating Crohn disease. In retrospect, the fungus was found to be resistant to both of the aforementioned drugs and susceptible to voriconazole and posaconazole. The gastrointestinal findings raise the possibility of further dissemination of a partially treated Phialemonium infection.
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PMID:Lung infection due to opportunistic fungus, Phialemonium obovatum, in a bone marrow transplant recipient: an emerging infection with fungemia and Crohn disease-like involvement of the gastrointestinal tract. 1608 58

Imatinib and other Abl tyrosine kinase inhibitors (TKIs), such as dasatinib and nilotinib, have significantly improved the outcome of patients with chronic myeloid leukemia. Imatinib and dasatinib are currently Food and Drug Administration (FDA) approved, and nilotinib is expected to gain FDA approval soon. In addition, several other Abl TKIs are being evaluated in various clinical trials. Imatinib has also shown efficacy in the therapy of gastrointestinal stromal tumors, Philadelphia chromosome-positive acute lymphocytic leukemia and hypereosinophilic syndrome. Because of their efficacy, more patients will receive Abl TKIs for a longer period of time. Imatinib was FDA approved after a short follow-up because of its exceptional efficacy and safety profile. The most common adverse events reported included fluid retention, fatigue, diarrhea, and muscle cramps. With longer follow-up, issues related to the long-term use of imatinib have been discussed. Our aim is to review the emerging safety issues of Abl TKIs after a longer follow-up.
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PMID:Emerging safety issues with imatinib and other Abl tyrosine kinase inhibitors. 1738 19

This study was done to assess the overall response rate of imatinib mesylate in local patients with chronic myeloid leukaemia. A total of 69 patients were recruited with male/female ratio of 7:3. Of the 69 patients; 35% were in the chronic phase, 41% were in the accelerated phase, 17% were in blast crisis and the remaining 7% were after stem cell transplantation. Complete haematological response rates of patients in chronic phase, accelerated phase and blast crisis were 95.8%, 96.4% and 41.7% respectively. Thirty-eight percent of patients achieved complete cytogenetic response and 10% achieved partial cytogenetic response. The cytogenetic response rates were 80%, 41.7% and 18.2% in chronic, accelerated and blast crisis phase respectively (p < 0.005). Twenty-six percent of patients developed anaemia, 13% had neutropenia and 12% had thrombocytopenia after starting on treatment. In addition, 14% of patients developed peripheral oedema, 13% complained of musculoskeletal pain, 12% had gastrointestinal side effects which include nausea, vomiting and diarrhoea, 9% had grade 1 hepatotoxicity, 7% developed skin rashes and one patient had an abnormal renal function test. Patients taking 600mg or higher dosage of imatinib had more gastrointestinal side effects. Patients who weighed less than 60kg had a much higher risk of developing anaemia. Anaemia was a negative predictor of cytogenetic response. Presenting high white blood cell counts and absence of cytogenetic response were also negative predictors of survival. Overall survival was 87%. This was affected by the different phases of disease (chronic phase was better than accelerated and blast crisis) (p < 0.001). In conclusion, our local CML patients did well on treatment with imatinib.
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PMID:Imatinib mesylate in the treatment of chronic myeloid leukemia: a local experience. 1762 54

Vorinostat (suberoylanilide hydroxamic acid, SAHA) is a histone deacetylase inhibitor active clinically in cutaneous T-cell lymphoma and preclinically in leukemia. A phase 1 study was conducted to evaluate the safety and activity of oral vorinostat 100 to 300 mg twice or thrice daily for 14 days followed by 1-week rest. Patients with relapsed or refractory leukemias or myelodysplastic syndromes (MDS) and untreated patients who were not candidates for chemotherapy were eligible. Of 41 patients, 31 had acute myeloid leukemia (AML), 4 chronic lymphocytic leukemia, 3 MDS, 2 acute lymphoblastic leukemia, and 1 chronic myelocytic leukemia. The maximum tolerated dose (MTD) was 200 mg twice daily or 250 mg thrice daily. Dose-limiting toxicities were fatigue, nausea, vomiting, and diarrhea. Common drug-related adverse experiences were diarrhea, nausea, fatigue, and anorexia and were mild/moderate in severity. Grade 3/4 drug-related adverse experiences included fatigue (27%), thrombocytopenia (12%), and diarrhea (10%). There were no drug-related deaths; 7 patients had hematologic improvement response, including 2 complete responses and 2 complete responses with incomplete blood count recovery (all with AML treated at/below MTD). Increased histone acetylation was observed at all doses. Antioxidant gene expression may confer vorinostat resistance. Further evaluation of vorinostat in AML/MDS is warranted.
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PMID:Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. 1796 10

Dasatinib, a potent inhibitor of BCR-ABL in vitro, is effective for patients with chronic myelogenous leukemia (CML) resistant or intolerant to imatinib. To provide a more definitive assessment of dasatinib in chronic-phase (CP)-CML, we report extended follow-up of a phase II trial, presenting data for the entire patient cohort (N=387). Dasatinib (70 mg) twice daily was administered to patients with imatinib-resistant or -intolerant CP-CML. With median follow-up of 15.2 months (treatment duration, <1-18.4 months), a complete hematologic response was attained or maintained in 91% of patients. A major cytogenetic response (MCyR) was attained or maintained by 59% (52% imatinib resistant and 80% imatinib intolerant); this was complete in 49% of patients (40% imatinib resistant and 75% imatinib intolerant). Of 230 patients achieving an MCyR, 7 experienced disease progression. Fifteen-month progression-free survival was 90% while overall survival was 96%. Grade 3/4 thrombocytopenia and neutropenia were reported in 48 and 49% of patients, respectively. Non-hematologic toxicity (any grade) consisted primarily of diarrhea (37%), headache (32%), fatigue (31%), dyspnea (30%) and pleural effusion (27%). Pleural effusions were classified as grade 3 in 6% of reported events, with no incidence of grade 4. Dasatinib is associated with high response rates in patients with imatinib-resistant or -intolerant CP-CML.
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PMID:Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. 1840 16

Receptor activated tyrosine kinases such as c-kit, c-fms and PDGFR are known targets of inhibition by imatinib mesylate (Gleevec) and are expressed on AML blasts. Marrow stromal cells and monocytes express KIT ligand, M-CSF and PDGF and are therefore capable of activating survival pathways in these leukemic cells. Given the synergy in vitro between Ara-C and imatinib mesylate on AML cell growth inhibition, we initiated a Phase I study combining CLAG+imatinib mesylate in AML patients. Patients with relapsed, refractory AML or CML myeloid blast crisis were eligible to receive Cladribine 5mg/m(2) days 3-7, Cytarabine 2gm/m(2) days 3-7, G-CSF 300mcg days 2-7, and escalating doses of imatinib mesylate given on days 1-15. The level 1 Gleevec dose was 400mg, while level 2 was 600mg and the level 3 dose 800mg. A total of 16 patients were enrolled, 15 AML and 1 CML myeloid blast crisis. The dose escalation occurred as planned and there was no clear evidence of added toxicity due to imatinib mesylate. One patient with an extensive cardiac history died of cardiac causes on day 1 of therapy however no other deaths occurred within 30 days of starting therapy. One patient had a Grade 3 skin rash at dose level 2. The most common toxicities encountered during induction therapy were nausea, vomiting, rash and diarrhea that were transient and/or reversible. At the 800mg dose 1 patient developed a decline in cardiac ejection fraction on day 20 who later died of sepsis, so this was considered a dose limiting toxicity. Of 16 evaluable patients 11 achieved a hypocellular marrow after initial induction with 1 additional patient achieving a hypocellular marrow following a second course of the same regimen. Four patients (25%) achieved a complete morphologic response with normal cytogenetics, 2 patients (12.5%) achieved a complete morphologic response only and 1 patient had a complete response in the bone marrow but incomplete blood count recovery. The overall response rate was 43.8%. The median overall survival was 175 days (95% CI 16.24-333.76) and the median relapse free survival was 76 days. The addition of imatinib mesylate to CLAG was well tolerated with acceptable toxicities and response rates comparable to other salvage regimens. To assess the efficacy of imatinib mesylate in combination with CLAG, a larger phase II trial is now planned.
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PMID:Phase I study of cladribine, cytarabine (Ara-C), granulocyte colony stimulating factor (G-CSF) (CLAG Regimen) and simultaneous escalating doses of imatinib mesylate (Gleevec) in relapsed/refractory AML. 1857 21

Imatinib is a relatively specific inhibitor of the BCR/ABL tyrosine kinase, effective in chronic myeloid leukemia (CML). The aim of our study was to analyse the frequency and type of hematological and non-hematological adverse events in our series of late and early chronic phase patients with CML treated with imatinib and correlate the grade of hematological toxicity with the response obtained. Hematological events were seen in 59 out of 150 (39%) late chronic phase (CP) patients: of these, 24% experienced toxicity Grade 3-4. Of the 100 early CP patients, 26 (26%) had hematological adverse event: 7% experienced toxicity Grade 3-4 (p=0.0001). We found that only in early CP patients, the occurrence of hematological side effects of any grade within 6 months of therapy had a negative influence on cytogenetic response. We compared the incidence of non-hematological adverse events occurring in late and in early CP patients and found that in these latter, some side effects were more frequent, such as weight gain, periorbital edema, muscle cramps, skin rashes, diarrhea, weeping. On the contrary, we found that bone pain and hemorrhagic events were more common in late CP patients. Grade 3-4 adverse events were recorded at rates below 4% and decreased over time: in late CP patients hemorrhages and muscle cramps were the most common side effects of Grade 3-4, whereas in early CP patients, the most frequent events were nausea, weight gain and cutaneous rash. We have observed that hematological and non-hematological side effects during imatinib therapy are different among late and early CP patients and that severe hematological toxicity may influence cytogenetic response only in early CP patients.
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PMID:Differences in hematological and non-hematological toxicity during treatment with imatinib in patients with early and late chronic phase chronic myeloid leukemia. 1905 81

Aurora kinases (A, B and C) are proteins expressed only in cells which divide actively and their increase is a factor of bad prognosis in cancer. They regulate the maturation of centrosomes, the separation and the condensation of chromosomes, mitotic checkpoint and cytokinesis. The inhibition of aurora kinases, by powerful and selective inhibitors, is due to the formation of abnormal cells which are eliminated by apoptosis. The purpose of this article is to present the role, the antitumor activity and the tolerability of these inhibitors. They can be administered orally or intravenously, on weekly or monthly schedules. In our knowledge, twelve molecules are evaluated at the present time and will be discussed only the most advanced namely: VX-680, ZM 447439, MLN 8054, AZD 1152, PHA 739358, SU 6668 and AT 9283. The main indications are breast, colon, lung, pancreas and bladder cancers as well as hematologic tumors such as leukemia (ALL, AML, CML) and lymphoma. These inhibitors can be associated with other chemotherapies. They seem well tolerated; the reported side effects are digestive disorders (diarrhea), fever, asthenia, alopecia, slumber, neutropenia, myelosuppression and disturbance of the biological markers.
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PMID:[Inhibitors of aurora kinases]. 1929 89


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