| 1. |
- Ekberg, Jenny, et al.
(författare)
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Expression of cyclin A1 and cell cycle proteins in hematopoietic cells and acute myeloid leukemia and links to patient outcome
- 2005
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Ingår i: European Journal of Haematology. - : Wiley-Blackwell Publishing Inc.. - 0902-4441 .- 1600-0609. ; 75:2, s. 106-115
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Tidskriftsartikel (refereegranskat)abstract
- Abnormal expression of several key regulators essential for G1/S transitions has been implicated in tumorigenesis. A critical role of cyclin A1 in the development of acute myeloid leukemia (AML) has previously been demonstrated in transgenic mice. Our present study focused on the expression and prognostic significance of cyclin A1 and a panel of cell cycle regulatory proteins including cyclin A2, cyclin B1, cyclin E, CDK1, CDK2, p21 and p27 in bone marrow samples from 40 patients with AML. Freshly isolated CD34+ hematopoietic cells and bone marrow samples from 10 healthy donors were also assessed for cell type- and subcellular-specific expression of the cell cycle regulatory proteins. The level of cyclin A1 expression was the only factor that showed a significant correlation with patient outcome. In log-rank test stratified by levels of cyclin A1 expression, patients with high levels of cyclin A1 had significantly worse overall survival (OS) (P = 0.012) compared to those with low levels. Further, patients with high levels of cyclin A1 had significantly lower disease-free survival (DFS) (P = 0.028). Multivariate analysis indicated that cyclin A1 protein expression was an independent prognostic factor for predicting DFS (P = 0.035) and OS (P = 0.045). No correlation between cyclin A1 expression and age was found. However, expression of cyclin A2, cyclin B1, cyclin E, CDK1, CDK2, p21 and p27 did not show prognostic significance in these AML patients.
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| 2. |
- Flygt, Hjalmar, et al.
(författare)
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Long-term tolerability and efficacy after initial PegIFN-alpha addition to dasatinib in CML-CP : Five-year follow-up of the NordCML007 study
- 2021
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Ingår i: European Journal of Haematology. - : Wiley-Blackwell. - 0902-4441 .- 1600-0609. ; 107:6, s. 617-623
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Treatment-free remission (TFR) has emerged as a treatment goal in chronic myeloid leukemia in the chronic phase (CML-CP). Attempts to increase proportion of patients achieving TFR include combination of tyrosine kinase inhibitors (TKI) and other drugs. Interferon-alpha in addition to TKI has shown promising efficacy but with dose-dependent toxicity and discontinuations. NordCML007 was initiated to study the efficacy and safety of low dose pegylated IFN-alpha (PegIFN-alpha) in combination with dasatinib (DAS) in CML-CP. Methods Forty patients with newly diagnosed CML-CP were given DAS upfront. After month 3 (M3) 15 mu g/wk of PegIFN-alpha was added and increased to 25 mu g/wk from M7 until M15. DAS treatment was continued and adverse events and BCR-ABL1 qRT-PCR values were reported yearly after M24. Results from M1 to M18 have previously been published, and here we present long-term data. Results After 5 years of follow-up, there were no suspected unexpected serious adverse reactions, no increase in serosal effusions, no disease progressions and no CML-related deaths. Rates of MR3.0 (MMR), MR4.0 and MR4.5 were 84.6%, 64.1% and 51.3% respectively at M60, and 95% of patients reached MMR at some point during the study. Conclusion Initial addition of PegIFN-alpha to DAS shows good long-term efficacy without increased toxicity.
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| 3. |
- Flygt, Hjalmar, et al.
(författare)
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Long-term tolerability and efficacy after initial PegIFN-α addition to dasatinib in CML-CP : Five-year follow-up of the NordCML007 study
- 2021
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Ingår i: European Journal of Haematology. - : John Wiley & Sons. - 0902-4441 .- 1600-0609. ; 107:6, s. 617-623
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesTreatment-free remission (TFR) has emerged as a treatment goal in chronic myeloid leukemia in the chronic phase (CML-CP). Attempts to increase proportion of patients achieving TFR include combination of tyrosine kinase inhibitors (TKI) and other drugs. Interferon-α in addition to TKI has shown promising efficacy but with dose-dependent toxicity and discontinuations. NordCML007 was initiated to study the efficacy and safety of low dose pegylated IFN-α (PegIFN-α) in combination with dasatinib (DAS) in CML-CP.MethodsForty patients with newly diagnosed CML-CP were given DAS upfront. After month 3 (M3) 15 μg/wk of PegIFN-α was added and increased to 25 μg/wk from M7 until M15. DAS treatment was continued and adverse events and BCR-ABL1 qRT-PCR values were reported yearly after M24. Results from M1 to M18 have previously been published, and here we present long-term data.ResultsAfter 5 years of follow-up, there were no suspected unexpected serious adverse reactions, no increase in serosal effusions, no disease progressions and no CML-related deaths. Rates of MR3.0 (MMR), MR4.0 and MR4.5 were 84.6%, 64.1% and 51.3% respectively at M60, and 95% of patients reached MMR at some point during the study.ConclusionInitial addition of PegIFN-α to DAS shows good long-term efficacy without increased toxicity.
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| 4. |
- Gunnarsson, Niklas, et al.
(författare)
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Population-based assessment of chronic myeloid leukemia in Sweden : striking increase in survival and prevalence
- 2016
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 97:4, s. 387-392
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Tidskriftsartikel (refereegranskat)abstract
- The clinical outcome for patients with chronic myeloid leukemia (CML) has improved dramatically following the introduction of tyrosine kinase inhibitors. An improved survival, combined with a constant incidence, is expected to increase the prevalence of CML. However, data on the prevalence of CML remain scarce. We examined the overall and relative (age and gender matched) survival and assessed the past, present, and projected future prevalence of CML in Sweden. Data on all patients diagnosed with CML between 1970 and 2012 were retrieved from the Swedish Cancer Register and the Swedish Cause of Death Register. The 5-year overall survival increased from 0.18 to 0.82, during the observed time period. Between 2006 and 2012, the 5-year relative survival was close to normal for 40-year-old, but considerably lower for 80-year-old CML patients. The observed prevalence tripled from 1985 to 2012, from 3.9 to 11.9 per 100 000 inhabitants. Assuming no further improvements in relative survival, the prevalence is projected to further increase by 2060 to 22.0 per 100 000 inhabitants (2587 persons in Sweden). The projected dramatic increase in CML prevalence has major medical and health economic implications and needs to be considered in planning how to organize future care of CML patients.
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| 5. |
- Hjorth-Hansen, Henrik, et al.
(författare)
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Dasatinib induces fast and deep responses in newly diagnosed chronic myeloid leukaemia patients in chronic phase: clinical results from a randomised phase-2 study (NordCML006)
- 2015
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Ingår i: European Journal of Haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 94:3, s. 243-250
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Tidskriftsartikel (refereegranskat)abstract
- We randomised 46 newly diagnosed patients with chronic myeloid leukaemia (median age 56) to receive dasatinib 100mg QD or imatinib 400mg QD and report outcome as an intention-to-treat analysis with 36months follow-up. Early cytogenetic and molecular responses were superior in the dasatinib group, with a tendency that imatinib patients caught up with time. For instance, MR3.0 was reached at 3months in 36% vs. 8% (P=0.02), at 12months in 81% vs. 46% (P=0.02) and at 18months in 73% vs. 65% (n.s.) of the patients in the two groups. In contrast, MR4.5 was consistently superior in the dasatinib group at all time points from 6months onwards, reaching 61% vs. 21% (P<0.05) at 36months. Sixty-four vs. 71% of the patients in the dasatinib and imatinib arms, respectively, remained on assigned drug. Dasatinib dose was frequently reduced, but with maintained excellent effect. One imatinib patient progressed to blastic phase, but no CML-related deaths occurred. In conclusion, our data compare favourably with those of the dasatinib registration study, DASISION. The fast and deep molecular responses induced by dasatinib compared with imatinib may be exploited to increase the proportion of patients who can achieve a treatment-free remission after treatment discontinuation.
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| 6. |
- Larfors, Gunnar, et al.
(författare)
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The impact of socio-economic factors on treatment choice and mortality in chronic myeloid leukaemia
- 2017
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 98:4, s. 398-406
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To evaluate the influence of socio-economic variables on treatment selection and survival of patients with chronic myeloid leukaemia (CML).METHODS: Using information available in population-based Swedish registries, we evaluated indices of health, education and economy from the 980 patients in the Swedish CML register diagnosed between 2002 and 2012. Apart from internal comparisons, five age-, gender- and region-matched control subjects per patient served as control cohort. Median follow-up time from CML diagnosis was 4.8 years.RESULTS: Among patients with CML, low personal or household income, short education, living alone, poor performance status and high age (>60 years) were significantly associated with an inferior survival (in univariate analyses). However, similar findings were noted also in the matched control group, and in comparisons adjusted for calendar year, age and performance status, socio-economic variables were not significantly associated with CML survival. Meanwhile, both education and income were independently linked to TKI treatment overall and to upfront treatment with second-generation TKIs.CONCLUSIONS: In conclusion, socio-economic conditions were associated with survival in the studied CML cohort but these associations could be explained by differences at baseline. Meanwhile, socio-economic conditions appeared to influence treatment choice.
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| 7. |
- Söderlund, Stina, et al.
(författare)
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Advanced phase chronic myeloid leukaemia (CML) in the tyrosine kinase inhibitor era : a report from the Swedish CML register
- 2017
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 98:1, s. 57-66
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The primary goal in management of chronic phase (CP) chronic myeloid leukaemia (CML) is to prevent disease progression to accelerated phase (AP) or blast crisis (BC). We have evaluated progression rates in a decentralised healthcare setting and characterised patients progressing to AP/BC on TKI treatment.METHODS: Using data from the Swedish CML register, we identified CP-CML patients diagnosed 2007-2011 who progressed to AP/BC within 2 yrs from diagnosis (n = 18) as well as patients diagnosed in advanced phase during 2007-2012 (n = 36) from a total of 544 newly diagnosed CML cases. We evaluated baseline characteristics, progression rates, outcome and adherence to guidelines for monitoring and treatment.RESULTS: The cumulative progression rate at 2 yrs was 4.3%. All 18 progression cases had been treated with imatinib, and six progressed within 6 months. High-risk EUTOS score was associated to a higher risk of progression. Insufficient cytogenetic and/or molecular monitoring was found in 33%. Median survival after transformation during TKI treatment was 1.4 yrs. In those presenting with BC and AP, median survival was 1.6 yrs and not reached, respectively.CONCLUSION: In this population-based setting, progression rates appear comparable to that reported from clinical trials, with similar dismal patient outcome. Improved adherence to CML guidelines may minimise the risk of disease progression.
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| 8. |
- Montano, Carmen, et al.
(författare)
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Forced expression of human macrophage colony-stimulating factor in CD34+ cells promotes monocyte differentiation in vitro and in vivo but blunts osteoclastogenesis in vitro
- 2017
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441.
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Here, we tested the hypothesis that human M-CSF (hM-CSF) overexpressed in cord blood (CB) CD34+ cells would induce differentiation and survival of monocytes and osteoclasts in vitro and in vivo. Methods: Human M-CSF was overexpressed in cord blood CD34+ cells using a lentiviral vector. Results: We show that LV-hM-CSF-transduced CB CD34+ cells expand 3.6- and 8.5-fold more with one or two exposures to the hM-CSF-expressing vector, respectively, when compared to control cells. Likewise, LV-hM-CSF-transduced CB CD34+ cells show significantly higher levels of monocytes. In addition, these cells produced high levels of hM-CSF. Furthermore, they are able to differentiate into functional bone-resorbing osteoclasts in vitro. However, osteoclast differentiation and bone resorption were blunted compared to control CD34+ cells receiving exogenous hM-CSF. NSG mice engrafted with LV-hM-CSF-transduced CB CD34+ cells have physiological levels of hM-CSF production that result in an increase in the percentage of human monocytes in peripheral blood and bone marrow as well as in the spleen, lung and liver. Conclusion: In summary, ectopic production of human M-CSF in CD34+ cells promotes cellular expansion and monocyte differentiation in vitro and in vivo and allows for the formation of functional osteoclasts, albeit at reduced levels, without an exogenous source of M-CSF, in vitro.
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