| 1. |
- Hochhaus, A, et al.
(författare)
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Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia.
- 2009
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 23:6, s. 1054-61
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Tidskriftsartikel (refereegranskat)abstract
- Imatinib mesylate is considered standard of care for first-line treatment of chronic phase chronic myeloid leukemia (CML-CP). In the phase III, randomized, open-label International Randomized Study of Interferon vs STI571 (IRIS) trial, previously untreated CML-CP patients were randomized to imatinib (n=553) or interferon-alpha (IFN) plus cytarabine (n=553). This 6-year update focuses on patients randomized to receive imatinib as first-line therapy for newly diagnosed CML-CP. During the sixth year of study treatment, there were no reports of disease progression to accelerated phase (AP) or blast crisis (BC). The toxicity profile was unchanged. The cumulative best complete cytogenetic response (CCyR) rate was 82%; 63% of all patients randomized to receive imatinib and still on study treatment showed CCyR at last assessment. The estimated event-free survival at 6 years was 83%, and the estimated rate of freedom from progression to AP and BC was 93%. The estimated overall survival was 88% -- or 95% when only CML-related deaths were considered. This 6-year update of IRIS underscores the efficacy and safety of imatinib as first-line therapy for patients with CML.
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| 2. |
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| 3. |
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| 4. |
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| 5. |
- Kantarjian, Hagop M, et al.
(författare)
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Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase.
- 2009
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Ingår i: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 115:3, s. 551-60
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Tidskriftsartikel (refereegranskat)abstract
- Imatinib mesylate given orally at a daily dose of 400 mg is the standard of care as initial therapy for patients with chronic myeloid leukemia (CML) in chronic phase (CML-CP). Treatment guidelines propose dose escalation based on clinical assessments of disease response.
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| 6. |
- Larson, Richard A, et al.
(författare)
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Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study.
- 2008
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 111:8, s. 4022-8
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Tidskriftsartikel (refereegranskat)abstract
- Imatinib at 400 mg daily is standard treatment for chronic myeloid leukemia in chronic phase. We here describe the correlation of imatinib trough plasma concentrations (C(mins)) with clinical responses, event-free survival (EFS), and adverse events (AEs). Trough level plasma samples were obtained on day 29 (steady state, n = 351). Plasma concentrations of imatinib and its metabolite CGP74588 were determined by liquid chromatography/mass spectrometry. The overall mean (+/- SD, CV%) steady-state C(min) for imatinib and CGP74588 were 979 ng/mL (+/- 530 ng/mL, 54.1%) and 242 ng/mL (+/- 106 ng/mL, 43.6%), respectively. Cumulative estimated complete cytogenetic response (CCyR) and major molecular response (MMR) rates differed among the quartiles of imatinib trough levels (P = .01 for CCyR, P = .02 for MMR). C(min) of imatinib was significantly higher in patients who achieved CCyR (1009 +/- 544 ng/mL vs 812 +/- 409 ng/mL, P = .01). Patients with high imatinib exposure had better rates of CCyR and MMR and EFS. An exploratory analysis demonstrated that imatinib trough levels were predictive of higher CCyR independently of Sokal risk group. AE rates were similar among the imatinib quartile categories except fluid retention, rash, myalgia, and anemia, which were more common at higher imatinib concentrations. These results suggest that an adequate plasma concentration of imatinib is important for a good clinical response. This study is registered at http://clinicaltrials.gov as NCT00333840.
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| 7. |
- Malmeström, Clas, 1965, et al.
(författare)
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Relapses in multiple sclerosis are associated with increased CD8+ T-cell mediated cytotoxicity in CSF.
- 2008
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Ingår i: Journal of neuroimmunology. - : Elsevier BV. - 0165-5728. ; 196:1-2, s. 159-65
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Tidskriftsartikel (refereegranskat)abstract
- MS is thought to be mediated by CD4(+) T-helper cells. To investigate the importance of CD8(+) cytotoxic T-cells in MS we analyzed peripheral blood T-cells by DNA microarray, and plasma and CSF levels of granzymes from MS patients and controls. Cytotoxic gene expression was decreased in peripheral T-cells from RRMS patients whereas plasma levels of granzymes were unchanged. However, granzyme levels were elevated in the CSF of RRMS patients at relapse compared with controls and remission. Thus, CD8+ T-cell-mediated cytotoxicity is confined to the CSF/CNS compartment in RRMS patients and may be involved in the immunopathogenesis of clinical relapses.
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| 8. |
- Olsson, Bob, 1969, et al.
(författare)
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Disturbed apoptosis of T-cells in patients with active idiopathic thrombocytopenic purpura.
- 2005
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Ingår i: Thrombosis and haemostasis. - 0340-6245. ; 93:1, s. 139-44
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Tidskriftsartikel (refereegranskat)abstract
- Idiopathic thrombocytopenic purpura (ITP) is an organ specific autoimmune disorder in which T-lymphocyte abnormalities have pathogenetic importance. In a DNA microarray screen of CD3+ T-lymphocytes from ITP patients and healthy controls we found an altered expression of genes associated with apoptosis, e.g. A20, caspase-8 and Bax. This together with our previous findings of increased gene expression of Fas, interferon-g and IL-2 receptor beta (IL2RB) indicated an altered activation induced cell death (AICD) of T-cells in ITP. Using a proliferation assay we found that CD3+ lymphocytes from ITP patients were significantly more resistant to dexamethasone induced suppression compared to normal lymphocytes. We also found that cultured CD3+ lymphocytes from ITP patients in remission were more susceptible to apoptosis both in the presence and absence of dexamethasone compared to cells from patient with active ITP and healthy controls, as indicated by increased staining of AnnexinV binding. Our findings suggest that apoptotic resistance of activated T-lymphocytes in patients with active ITP may lead to defective clearance of autoreactive T-lymphocytes through AICD, which might cause a continued immune destruction of platelets. Conversely, a loss of resistance to AICD in ITP patients in remission might be an important mechanism for the achievement of remission.
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| 9. |
- Olsson, Bob, 1969, et al.
(författare)
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Recruitment of T cells into bone marrow of ITP patients possibly due to elevated expression of VLA-4 and CX3CR1.
- 2008
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 112:4, s. 1078-84
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Tidskriftsartikel (refereegranskat)abstract
- In idiopathic thrombocytopenic purpura (ITP), platelets are destroyed in the spleen, liver, and bone marrow (BM) by autoantibodies and cytotoxic T cells. In a DNA microarray screen of peripheral blood T cells, we found that VLA-4, CX3CR1, and CXCR4, involved in T-cell homing, had increased expression in ITP patients compared with controls. However, we only found increased protein expression of VLA-4 on T cells from peripheral blood by flow cytometry. To address a possible recruitment of T cells into the organs involved in platelet destruction, we analyzed T cells in BM. In BM, T-cell surface expression of VLA-4 and CX3CR1 was increased in ITP patients compared with controls. Furthermore, the number of CD3(+) T cells in BM, but not in blood, was increased in ITP patients compared with controls. This finding was confirmed by immunohistochemistry of BM biopsies. The number of regulatory T cells (CD4(+)/CD25(bright)) was decreased in the BM of ITP patients, whereas Fas expression was increased. In conclusion, ITP is associated with accumulation and activation of T cells in the BM. Recruitment of T cells into the target organ (eg, BM) is plausible and may be facilitated through increased VLA-4 and CX3CR1 expression. These molecules might serve as new treatment targets in ITP.
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| 10. |
- Wei, Yuan, 1978, et al.
(författare)
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Changes in expression of apoptosis-related genes are linked to the molecular response to imatinib treatment in chronic-phase chronic myeloid leukemia patients.
- 2007
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Ingår i: Acta haematologica. - : S. Karger AG. - 1421-9662 .- 0001-5792. ; 117:2, s. 83-90
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Tidskriftsartikel (refereegranskat)abstract
- Most patients with a chronic phase of chronic myeloid leukemia (CML) treated with imatinib mesylate achieve a cytogenetic remission, but in the majority, residual disease is detectable by RT-PCR. The mechanisms by which residual leukemic cells survive imatinib treatment are unresolved. However, induction of apoptosis in leukemic stem cells and immunotherapy are currently under investigation. We studied the mRNA expression of apoptosis-related genes in peripheral blood mononuclear cells from chronic-phase CML patients before imatinib treatment. It was found that their BCL2 and BAD expression was significantly different compared to the normal controls, and a lower BAD expression was associated with a better molecular response to imatinib treatment at 12 months.
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