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- Eriksson, Mia, et al.
(författare)
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Agonistic targeting of TLR1/TLR2 induces p38 MAPK-dependent apoptosis and NFκB-dependent differentiation of AML cells
- 2017
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 1:23, s. 2046-2057
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Tidskriftsartikel (refereegranskat)abstract
- Acute myeloid leukemia (AML) is associated with poor survival, and there is a strong need to identify disease vulnerabilities that might reveal new treatment opportunities. Here, we found that Toll-like receptor 1 (TLR1) and TLR2 are upregulated on primary AML CD34+CD38-cells relative to corresponding normal bone marrow cells. Activating the TLR1/TLR2 complex by the agonist Pam3CSK4 inMLL-AF9-driven human AML resulted in induction of apoptosis by p38 MAPK-dependent activation of Caspase 3 and myeloid differentiation in a NFκB-dependent manner. By using murineTrp53 -/- MLL-AF9AML cells, we demonstrate that p53 is dispensable for Pam3CSK4-induced apoptosis and differentiation. Moreover, murineAML1-ETO9a-driven AML cells also were forced into apoptosis and differentiation on TLR1/TLR2 activation, demonstrating that the antileukemic effects observed were not confined toMLL-rearranged AML. We further evaluated whether Pam3CSK4 would exhibit selective antileukemic effects. Ex vivo Pam3CSK4 treatment inhibited murine and human leukemia-initiating cells, whereas murine normal hematopoietic stem and progenitor cells (HSPCs) were relatively less affected. Consistent with these findings, primary human AML cells across several genetic subtypes of AML were more vulnerable for TLR1/TLR2 activation relative to normal human HSPCs. In theMLL-AF9AML mouse model, treatment with Pam3CSK4 provided proof of concept for in vivo therapeutic efficacy. Our results demonstrate that TLR1 and TLR2 are upregulated on primitive AML cells and that agonistic targeting of TLR1/TLR2 forces AML cells into apoptosis by p38 MAPK-dependent activation of Caspase 3, and differentiation by activating NFκB, thus revealing a new putative strategy for therapeutically targeting AML cells.
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| 3. |
- Fløisand, Yngvar, et al.
(författare)
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Safety and Effectiveness of Vedolizumab in Patients with Steroid-Refractory GI Acute GvHD : A Retrospective Record Review
- 2019
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Ingår i: Biology of Blood and Marrow Transplantation. - : Elsevier BV. - 1083-8791. ; 25:4, s. 720-727
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Tidskriftsartikel (refereegranskat)abstract
- Allogeneic hematopoietic cell transplantation can be curative in patients with hematological malignancies but carries a significant risk of graft-versus-host disease (GvHD). There are no standard treatments for steroid-refractory (SR) gastrointestinal (GI) acute GvHD (aGvHD). This multicenter, international, retrospective medical record review aimed to evaluate the off-label use of vedolizumab, a gut-selective immunomodulator, for treatment of SR GI aGvHD. Data from medical records of patients were collected, and criteria for extraction included: no more than 1 allogeneic hematopoietic cell transplantation and at least 1 dose of vedolizumab as treatment for SR GI aGvHD (stage I-IV GI aGvHD following ≥1 previous treatment regimen containing ≥1 mg/kg methylprednisolone or equivalent). Descriptive analyses of response rate, overall survival (OS), and serious adverse effects (SAEs) were performed. Twenty-nine patients were identified from 7 sites and had received 1-10 doses of IV vedolizumab 300 mg (median 3 doses) as treatment for SR GI aGvHD. The overall response rate at 6-10 weeks after vedolizumab initiation was 64% and OS at 6 months was 54%. There were 29 SAEs including 12 infections; 3 SAEs were considered possibly related to vedolizumab (2 of which were infections). Thirteen SAEs were fatal, 1 of which was possibly vedolizumab-related. There were 8 non-serious infections with confirmed GI origin and 1 serious (in 8 patients); there was no apparent pattern in the timing of these infections relative to the initiation of vedolizumab treatment. Further data on the efficacy and safety of vedolizumab in this setting are required from prospective trials.
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- Lazarevic, Vladimir Lj, et al.
(författare)
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A novel t(2;17) in transformation of essential thrombocythemia to acute myelocytic leukemia.
- 2004
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Ingår i: Cancer Genetics and Cytogenetics. - 0165-4608 .- 1873-4456. ; 148:1, s. 77-9
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Tidskriftsartikel (refereegranskat)abstract
- A transformation of essential thrombocythemia to acute myelocytic leukemia (AML), myelodysplastic syndrome, or agnogenic myelocytic metaplasia is a relatively rare event. It occurs in 1%-4.5% of all patients with either treated or untreated essential thrombocythemia. Cytogenetic changes in the transformation to AML are common. We report the case of a patient treated for essential thrombocythemia with hydroxyurea for 49 months. He developed AML with a t(2;17), which to our knowledge has not been described in the literature.
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| 8. |
- Lazarevic, Vladimir Lj
(författare)
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Acute myeloid leukemia in patients we judge as being older and/or unfit
- 2021
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Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 290:2, s. 279-293
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Forskningsöversikt (refereegranskat)abstract
- Definition of older age in AML is arbitrary. In the context of the clinical studies, it starts with age ≥ 60 or ≥65 years and in recent years ≥70 or 75, depending on the selection of the studied population. In clinical practice, with older age we often mean that the patient is unfit for intensive chemotherapy. Higher age overlaps with categories such as worse performance status, unfitness, co-morbidities, poor-risk cytogenetics, adverse mutation patterns, age-related clonal hematopoiesis and specific disease ontogeny. Intensive induction therapy can result in prolonged overall survival, at least in a subset of elderly patients aged up to 75 years despite the reluctance of some physicians and patients to use treatment regimens perceived as toxic. Venetoclax and azacytidine combination is the new standard of comparison for persons unfit for intensive therapy. New oral hypomethylating agent CC-486 as maintenance therapy led to a prolonged overall survival in a randomized trial of patients ≥ 55 years or age who were in first complete remission, not eligible for allogeneic stem cell transplantation. Any therapy is better than no therapy, but a substantial proportion of older patients still receive only palliative care. Making a decision for AML diagnosed in older age should be individualized and shared through the dialog with the patient and relatives or cohabitants, considering medical issues as well as social factors including personal goals. Although we are witnesses of the advances in basic research and therapy, we are still a very long way from curing older patients with AML.
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| 9. |
- Lazarevic, Vladimir Lj, et al.
(författare)
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Acute myeloid leukemia in very old patients
- 2018
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Ingår i: Haematologica. - Pavia, Italy : Fondazione Ferrata Storti. - 0390-6078 .- 1592-8721. ; 103:12, s. E578-E580
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
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