| 1. |
- Abé, Christoph, et al.
(author)
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Cytarabine dose intensification improves survival in older patients with secondary/high-risk acute myeloid leukemia in matched real-world versus clinical trial data
- 2024
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In: Leukemia and Lymphoma. - 1042-8194 .- 1029-2403.
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Journal article (peer-reviewed)abstract
- Since 1980’s, the established/standard treatment of acute myeloid leukemia (AML) is cytarabine infusion with anthracycline (7 + 3 regimen). We compared the 7 + 3 regimen in older secondary/high-risk AML patientsfrom a clinical trial with a matched population from the Swedish AML Registrytreated withan increased cytarabine dose in induction and consolidation as recommended in the Swedish National Guidelines since 2005. After successfulpropensity score matching, 104 patients per group were included. The primary outcome was overall survival (OS), and standard dosed patients had a median OS of 6.4 versus 10.7 months with increased dose intensity (hazard ratio:0.69, p = 0.012), with 5-year OS of 8.7% and 18.1%, andremission rates of 36% and 60%, respectively (p < 0.001). Median OS after allogeneic hematopoietic cell transplantation (in 27.9% per group) was 10.4 and 20.7 months, respectively. We conclude that the more intensive cytarabine schedule seems to provide improved outcomes inthe investigated AML patient group.
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| 2. |
- Angenendt, Linus, et al.
(author)
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Chromosomal Abnormalities and Prognosis in NPM1-Mutated Acute Myeloid Leukemia : A Pooled Analysis of Individual Patient Data From Nine International Cohorts
- 2019
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In: Journal of Clinical Oncology. - : AMER SOC CLINICAL ONCOLOGY. - 0732-183X .- 1527-7755. ; 37:29, s. 2632-2642
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Journal article (peer-reviewed)abstract
- PURPOSE: Nucleophosmin 1 (NPM1) mutations are associated with a favorable prognosis in acute myeloid leukemia (AML) when an internal tandem duplication (ITD) in the fms-related tyrosine kinase 3 gene (FLT3) is absent (FLT3-ITDneg) or present with a low allelic ratio (FLT3-ITDlow). The 2017 European LeukemiaNet guidelines assume this is true regardless of accompanying cytogenetic abnormalities. We investigated the validity of this assumption.METHODS: We analyzed associations between karyotype and outcome in intensively treated patients with NPM1(mut)/FLT3-ITDneg/low AML who were prospectively enrolled in registry databases from nine international study groups or treatment centers.RESULTS: Among 2,426 patients with NPM1(mut)/FLT3-ITDneg/low AML, 2,000 (82.4%) had a normal and 426 (17.6%) had an abnormal karyotype, including 329 patients (13.6%) with intermediate and 83 patients (3.4%) with adverse-risk chromosomal abnormalities. In patients with NPM1(mut)/FLT3-ITDneg/low AML, adverse cytogenetics were associated with lower complete remission rates (87.7%, 86.0%, and 66.3% for normal, aberrant intermediate, and adverse karyotype, respectively; P < .001), inferior 5-year overall (52.4%, 44.8%, 19.5%, respectively; P < .001) and event-free survival (40.6%, 36.0%, 18.1%, respectively; P < .001), and a higher 5-year cumulative incidence of relapse (43.6%, 44.2%, 51.9%, respectively; P = .0012). These associations remained in multivariable mixed-effects regression analyses adjusted for known clinicopathologic risk factors (P < .001 for all end points). In patients with adverse-risk chromosomal aberrations, we found no significant influence of the NPM1 mutational status on outcome.CONCLUSION: Karyotype abnormalities are significantly associated with outcome in NPM1(mut)/FLT3-ITDneg/low AML. When adverse-risk cytogenetics are present, patients with NPM1(mut) share the same unfavorable prognosis as patients with NPM1 wild type and should be classified and treated accordingly. Thus, cytogenetic risk predominates over molecular risk in NPM1(mut)/FLT3-ITDneg/low AML.
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| 3. |
- Benediktsson, Sigurdur, et al.
(author)
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Linear decline of corrected platelet count increment within 24 hours after platelet transfusion in haematological patients : a prospective observational study
- 2017
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In: European Journal of Haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; , s. 559-568
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Journal article (peer-reviewed)abstract
- OBJECTIVES: The aim of the present study was to prospectively explore the detailed longitudinal development of platelet increments in patients with chemotherapy-induced bone marrow aplasia during the first 24 hours after platelet transfusion.METHODS: Patients admitted to the Haematology department during 7 months and fulfilled inclusion criteria were divided into 4 groups: Group 1, patients with acute leukaemia; Group 2, patients after autologous stem cell transplantation (SCT); Group 3, patients after allogeneic SCT; Group 4, patients given platelet transfusion prior to intervention. We used frequent blood sampling within 24 hours after platelet transfusion to investigate the kinetics of platelet counts following transfusion.RESULTS AND CONCLUSIONS: 54 platelet transfusion occasions in patients with chemotherapy-induced bone marrow aplasia were included. The decrease of corrected count increment (CCI) 1-24 hours after platelet transfusions in all groups could be described as linear functions. For patients in the aggregated Groups 1-3, the decline was 2.0%± 0.6% (mean± standard deviation) per hour. For patients in Group 4, the decline of CCI was 2.8%± 1.2% per hour. We found no differences between the groups, either in the rate of platelet elimination from the bloodstream or in the mean CCI, in the first 24 hours post-transfusion. This article is protected by copyright. All rights reserved.
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| 4. |
- Berglund, Eva Caroline, et al.
(author)
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A Study Protocol for Validation and Implementation of Whole-Genome and -Transcriptome Sequencing as a Comprehensive Precision Diagnostic Test in Acute Leukemias
- 2022
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In: Frontiers in Medicine. - Lausanne, Switzerland : Frontiers Media SA. - 2296-858X. ; 9, s. 1-9
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Journal article (peer-reviewed)abstract
- Background: Whole-genome sequencing (WGS) and whole-transcriptome sequencing (WTS), with the ability to provide comprehensive genomic information, have become the focal point of research interest as novel techniques that can support precision diagnostics in routine clinical care of patients with various cancer types, including hematological malignancies. This national multi-center study, led by Genomic Medicine Sweden, aims to evaluate whether combined application of WGS and WTS (WGTS) is technically feasible and can be implemented as an efficient diagnostic tool in patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). In addition to clinical impact assessment, a health-economic evaluation of such strategy will be performed. Methods and Analysis: The study comprises four phases (i.e., retrospective, prospective, real-time validation, and follow-up) including approximately 700 adult and pediatric Swedish AML and ALL patients. Results of WGS for tumor (90×) and normal/germline (30×) samples as well as WTS for tumors only will be compared to current standard of care diagnostics. Primary study endpoints are diagnostic efficiency and improved diagnostic yield. Secondary endpoints are technical and clinical feasibility for routine implementation, clinical utility, and health-economic impact. Discussion: Data from this national multi-center study will be used to evaluate clinical performance of the integrated WGTS diagnostic workflow compared with standard of care. The study will also elucidate clinical and health-economic impacts of a combined WGTS strategy when implemented in routine clinical care. Clinical Trial Registration: [https://doi.org/10.1186/ISRCTN66987142], identifier [ISRCTN66987142].
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| 5. |
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| 6. |
- Colović, M, et al.
(author)
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Acute megakaryoblastic leukaemia in a patient with systemic lupus erythematosus
- 1997
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In: Medical Oncology. - 1357-0560. ; 14:1, s. 4-31
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Journal article (peer-reviewed)abstract
- We describe here a 72-year-old female patient with an acute megakaryoblastic leukaemia (M7 by FAB Classification) and systemic lupus erythematosus (SLE). The patient had not been pretreated with immunosuppressive therapy, which is potentially leukaemogenic. The karyotype displayed multiple, structural and numerical anomalies, suggesting a possible de novo rather than a secondary nature of leukaemia.
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| 7. |
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| 8. |
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| 9. |
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| 10. |
- Eriksson, Mia, et al.
(author)
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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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In: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 1:23, s. 2046-2057
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Journal article (peer-reviewed)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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| 11. |
- Fløisand, Yngvar, et al.
(author)
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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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In: Biology of Blood and Marrow Transplantation. - : Elsevier BV. - 1083-8791. ; 25:4, s. 720-727
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Journal article (peer-reviewed)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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| 12. |
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| 13. |
- Hulegardh, Erik, et al.
(author)
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Characterization and prognostic features of secondary acute myeloid leukemia in a population-based setting : A report from the Swedish Acute Leukemia Registry
- 2015
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In: American Journal of Hematology. - : Wiley-Blackwell. - 0361-8609 .- 1096-8652. ; 90:3, s. 208-214
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Journal article (peer-reviewed)abstract
- Patients with secondary acute myeloid leukemia (AML) often escape inclusion in clinical trials and thus, population-based studies are crucial for its accurate characterization. In this first large population-based study on secondary AML, we studied AML with an antecedent hematological disease (AHD-AML) or therapy-related AML (t-AML) in the population-based Swedish Acute Leukemia Registry. The study included 3,363 adult patients of which 2,474 (73.6%) had de novo AML, 630 (18.7%) AHD-AML, and 259 (7.7%) t-AML. Secondary AML differed significantly compared to de novo AML with respect to age, gender, and cytogenetic risk. Complete remission (CR) rates were significantly lower but early death rates similar in secondary AML. In a multivariable analysis, AHD-AML (HR 1.51; 95% CI 1.26-1.79) and t-AML (1.72; 1.38-2.15) were independent risk factors for poor survival. The negative impact of AHD-AML and t-AML on survival was highly age dependent with a considerable impact in younger patients, but without independent prognostic value in the elderly. Although patients with secondary leukemia did poorly with intensive treatment, early death rates and survival were significantly worse with palliative treatment. We conclude that secondary AML in a population-based setting has a striking impact on survival in younger AML patients, whereas it lacks prognostic value among the elderly patients. Am. J. Hematol. 90:208-214, 2015.
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| 14. |
- Jankovic, Gradimir, et al.
(author)
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Rates of nucleotide substitution, mutation at a locus, and the "beanbag" gene number in man
- 2002
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In: Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1434-5161 .- 1435-232X. ; 47:4, s. 4-202
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Journal article (peer-reviewed)abstract
- We estimated the number of different human genes by relating the patterns of spontaneous mutation at the population and individual level. A geometric distribution model of mutation was used in which the average rates of nucleotide replacement (P) and mutation at a locus (p), obtained by experiment, were used to determine the estimate of the physical size of the coding genome (n) in man. The probabilistic relation used, P = (1 - p)(n-1)p, integrates two different referential time scales of mutation, that of a nucleotide and year and that of a coding gene and generation. The estimates of n, for different values of P and p, are compatible with the experimentally determined genome sizes. The size of the coding portion of the genome appears to be evolutionarily constrained by an interplay between the rate of nucleotide replacement and the pattern of mutation at the level of the individual locus. The evolution of the size of the coding genome may be more dependent on the number of generations than on time.
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| 15. |
- Johansson, J-E, et al.
(author)
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Allogeneic haematopoietic stem-cell transplantation with reduced intensity conditioning for advanced stage Hodgkin's lymphoma in Sweden : high incidence of post transplant lymphoproliferative disorder
- 2011
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In: Bone Marrow Transplantation. - : Springer Science and Business Media LLC. - 0268-3369 .- 1476-5365. ; 46:6, s. 870-875
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Journal article (peer-reviewed)abstract
- Allogeneic transplantation after reduced intensity conditioning (allo-RIC) is a treatment option for patients with Hodgkin's lymphoma (HL) relapsing after autologous transplantation. In all, 23 adult patients with HL underwent allo-RIC in Sweden between 2000 and 2007. The median number of previous treatment lines was five and 20 patients (87%) were previously autografted. TRM at 100 days and at 1 year was 13 and 22% respectively. Acute GVHD grades II-IV developed in 7 out of 23 patients (30%) and chronic GVHD in 10 out of 20 patients at risk (50%). The OS and EFS at three years was 59 and 27%, respectively. Four patients (17%) developed post transplant lymphoproliferative disease (PTLD) after a median time of 55 days (range 38-95); two of these patients later died. The study confirmed that allo-RIC is feasible, but associated with a substantial relapse rate: only 20% of the patients were still alive 7 years after the transplant. A finding of high incidence of PTLD needs to be confirmed in a larger trial that includes patients with non-HL and CLL.
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| 16. |
- Juliusson, Gunnar, et al.
(author)
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Acute myeloid leukemia in the real world : why population-based registries are needed
- 2012
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In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 119:17, s. 3890-3899
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Journal article (peer-reviewed)abstract
- Population-based registries may provide data complementary to that from basic science and clinical intervention studies, all of which are essential for establishing recommendations for the management of patients in the real world. The same quality criteria apply for the evidence-based label, and both high representation and good data quality are crucial in registry studies. Registries with high coverage of the target population reduce the impact of selection on outcome and the subsequent problem with extrapolating data to nonstudied populations. Thus, data useful for clinical decision in situations not well covered by clinical studies can be provided. The potential clinical impact of data from population-based studies is exemplified with analyses from the Swedish Acute Leukemia Registry containing more than 3300 acute myeloid leukemia (AML) patients diagnosed between 1997 and 2006 with a median follow-up of 6.2 years on (1) the role of intensive combination chemotherapy for older patients with AML, (2) the impact of allogeneic stem cell transplantation on survival of younger patients with AML, and (3) the continuing problem with early deaths in acute promyelocytic leukemia. We also present the first Web-based dynamic graph showing the complex interaction between age, performance status, the proportion of patients given intensive treatment, early death rate, complete remission rate, use of allogeneic transplants, and overall survival in AML (non-AML).
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| 17. |
- Juliusson, Gunnar, et al.
(author)
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Epidemiology and Etiology of AML
- 2021
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In: Acute Myeloid Leukemia. - Cham : Springer International Publishing. - 2197-9774 .- 2197-9766. - 9783030726768 - 9783030726782 ; , s. 1-22
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Book chapter (peer-reviewed)abstract
- Acute myeloid leukemia (AML) is a grave disease with an incidence of 4 per 100,000 a year. It can present in all ages, but the median age is 70 years. One-third of such patients have secondary AML, that is, AML following chemoradiotherapy or a transformation from previous myelodysplastic syndrome (MDS) or myeloproliferative neoplasia. A combination of genetic, epigenetic, and environmental factors may be responsible for the development of most cases of AML. The pathogenesis of AML is characterized by the serial acquisition of somatic mutations and several genes are recurrently mutated in AML. Exposures to benzene, cigarette smoking, pesticides, embalming fluids, accidental or professional ionization radiation, therapeutic radiotherapy, and radioactive I-131 therapy can cause AML with or without a preceding MDS phase. Alkylating agents (e.g., melphalan, cyclophosphamide), topoisomerase-II inhibitors (e.g., etoposide, doxorubicin), and other drugs (e.g., azathioprine) are described to be associated with the development of therapy-related AML (t-AML). Furthermore, about 5–15% of adults and 4–13% of pediatric patients with MDS or AML carry germline pathogenic variants in cancer susceptibility genes. Individuals with clonal hematopoiesis (CHIP) progress to AML at a rate of about 1% per year. Higher age of onset, obesity, previous autoimmune disease, and antecedent MDS or MPN are associated with a risk for developing AML.
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| 18. |
- Juliusson, Gunnar, et al.
(author)
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Hematopoietic Stem Cell Transplantation Rates and Long-Term Survival in Acute Myeloid and Lymphoblastic Leukemia Real-World Population-Based Data From the Swedish Acute Leukemia Registry 1997-2006
- 2011
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In: Cancer. - Philadelphia : Wiley-Blackwell. - 0008-543X .- 1097-0142. ; 117:18, s. 4238-4246
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Journal article (peer-reviewed)abstract
- BACKGROUND: Allogeneic stem cell transplantation (alloSCT) reduces relapse rates in acute leukemia, but outcome is hampered by toxicity. Population-based data avoid patient selection and may therefore substitute for lack of randomized trials. METHODS: We evaluated alloSCT rates within the Swedish Acute Leukemia Registry, including 3899 adult patients diagnosed from 1997 through 2006 with a coverage of 98% and a median follow-up of 6.2 years. RESULTS: AlloSCT rates and survival decreased rapidly with age andgt;55 years. The 8-year overall survival (OS) was 65% in patients andlt;30 years and 38% in patients andlt;60 years and was similar for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Among 1073 patients andlt;60 years, alloSCT was performed in 42% and 49% of patients with AML and ALL, respectively. Two-thirds of the alloSCTs were performed in first complete remission, and half used unrelated donors, the same in AML and ALL. Regional differences in management and outcome were found: 60% of AML patients andlt;40 years received alloSCT in all parts of Sweden, but two-thirds of AML patients 40-59 years had alloSCT in one region compared with one-third in other regions (Pandlt;.001), with improved 8-year OS among all AML patients in this age cohort (51% vs 30%; P = .005). CONCLUSIONS: More Swedish AML patients received alloSCT, and long-term survival was better than in recently published large international studies, despite our lack of selection bias. There was no correlation between alloSCT rate and survival in ALL. In adult AML patients andlt;60 years of age, a high alloSCT rate was associated with better long-term survival, but there was no such correlation in ALL.
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| 19. |
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| 20. |
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| 21. |
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| 22. |
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| 23. |
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| 24. |
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| 25. |
- Juliusson, Gunnar, et al.
(author)
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The prognostic impact of FLT3-ITD and NPM1 mutation in adult AML is age-dependent in the population-based setting
- 2020
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In: Blood Advances. - : AMER SOC HEMATOLOGY. - 2473-9529 .- 2473-9537. ; 4:6, s. 1094-1101
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Journal article (peer-reviewed)abstract
- In acute myeloid leukemia (AML) FLT3 internal tandem duplication (ITD) and nucleophosmin 1 (NPM1) mutations provide prognostic information with clinical relevance through choice of treatment, but the effect of age and sex on these molecular markers has not been evaluated. The Swedish AML Registry contains data on FLT3-ITD and NPM1 mutations dating to 2007, and 1570 adult patients younger than 75 years, excluding acute promyelocytic leukemia, had molecular results reported. Females more often had FLT3(ITD) and/or NPM1(mut) (FLT3(ITD) : female, 29%; male, 22% [P - .00151; NPM1(mut) : female, 36%; male, 27% [P < .0001]), and more males were double negative (female, 53%; male, 64%; P < .0001). Patients with FLT3(ITD) were younger than those without (59 vs 62 years; P = .023), in contrast to patients with NPM1(mut) (62 vs 60 years; P = .059). Interestingly, their prognostic effect had a strong dependence on age: FLT3(ITD) indicated poor survival in younger patients (<60 years; P = .00003), but had no effect in older patients (60-74 years; P = .5), whereas NPM1(mut) indicated better survival in older patients (P = .00002), but not in younger patients (P = .95). In FLT3(ITD)/NPM1(mut) patients, the survival was less dependent on age than in the other molecular subsets. These findings are likely to have clinical relevance for risk grouping, study design, and choice of therapy.
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| 26. |
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| 27. |
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| 28. |
- Lazarevic, Vladimir
(author)
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Cytogenetic abnormalities in Acute Myeloid Leukemia in Sweden. A population based study.
- 2015
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Doctoral thesis (other academic/artistic)abstract
- The impact of cytogenetic findings in AML was analyzed in the large population-based Swedish AML registry. Karyotypic patterns differed by age: t(8;21), inv(16) and t(11q23) were more common in younger patients, whereas loss of 5q, 7q and 17p, monosomal karyotype (MK) and complex karyotype (CK) were more common in older patients. Patients with ≥5 chromosome abnormalities had worse overall survival than those with fewer abnormalities or normal karyotype in all age groups. Loss of 5q, 7q and/or 17p had, in contrast to MK, a further negative impact on survival. Multivariable analyses on risk factors in patients <80 years with cytogenetic abnormalities and intensive treatment revealed that age and performance status had the most significant impact on survival (both P<0.001), followed by sex (P=0.0135) and a karyotype including -7/del(7q) (P=0.048). We compared outcome of AHD-AML and tAML, i.e., secondary (sAML) with de novo AML. The CR rates were significantly lower but early death rates similar in sAML vs de novo AML. In a multivariable analysis, AHD-AML (HR 1.51; 95% CI 1.26–1.79) and tAML (1.72; 1.38–2.15) were independent risk factors for poor survival. The negative impact of AHD-AML and tAML on survival was highly age dependent with a considerable impact in younger patients, but without independent prognostic value in the elderly. The frequencies of unsuccessful cytogenetics (UC) and unperformed cytogenetics (UPC) were 2.1% and 2.0%, respectively. The early death rates differed between the cytogenetic subgroups (P=0.006) with the highest rates in patients with UC (14%) and UPC (12%) followed by high-risk (HR) AML, intermediate risk (IR) and standard risk (SR) cases successfully karyotyped (8.6%, 5.9%, and 5.8%, respectively). The CR rate was lower in UC and UPC and HR compared with the other risk groups (P<0.001). The 5-year OS rates were 25% for UC and 22% for UPC, whereas the corresponding frequencies for SR, IR and HR AML patients without UC and UPC were 64%, 31% and 15%, respectively. Lack of cytogenetic data translates into a poor prognosis. To ascertain the clinical implications of high hyperdiploid (HH; 49–65 chromosomes) and triploid/tetraploid (TT; >65 chromosomes) adult AML diagnosed 1997-2014, and 68 (1.9%) were HH (n=50)/TT (n=18). The OS was similar between patients with HH/TT and CK AML (median 0.9 years vs. 0.6 years; P=0.082), whereas OS was significantly longer (median 1.6 years; P=0.028) for IR AML. The OS was shorter for cases with HH than with TT (median 0.6 years vs. 1.4 years; P=0.032) and for HH/TT AMLs with adverse abnormalities (median 0.8 years vs. 1.1 years; P=0.044). HH/TT AML is associated with a poor outcome, but chromosome numbers >65 and absence of adverse aberrations seem to translate into a more favorable prognosis. Also, among 23 patients (0.4 %) with trisomy 13 with a median age of 72 years (44-84), there was a striking male predominance (80%) with AML-M0 subtype in 37% of patients. Therapy-related AML and MDS/MPN/AML were present in 30% of patients. Median OS time was 9.6 months (95 % CI (3.5-13.7), and 13 months for other patients (95% CI 11.7-14.04), which was almost identical as in previously published studies.
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| 29. |
- Lazarevic, Vladimir
(author)
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Enteric-coated mycophenolate sodium could be an alternative to methotrexate for GVHD prophylaxis.
- 2016
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In: European Journal of Haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 97:3, s. 213-214
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Journal article (peer-reviewed)abstract
- Morbidity and mortality resulting from acute and subsequently chronic graft-versus-host disease (GVHD) pose a serious challenge to wider applicability of allogeneic stem cell transplantation (SCT). Mycophenolate mofetil (MMF) is a widely used drug in combination with a calcineurin inhibitor and often cyclosporine (CsA), in preventing GVHD. The use of MMF for acute GVHD (aGVHD) prophylaxis appears to result in significantly faster platelet engraftment and a lower incidence of severe mucositis compared to methotrexate, which could reduce the length of hospital stay. However, there is no statistically significant difference between MMF and methotrexate in regards to relapse risk, non-relapse mortality, or overall survival(1) . This article is protected by copyright. All rights reserved.
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| 30. |
- Lazarevic, Vladimir, et al.
(author)
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Failure matters : unsuccessful cytogenetics and unperformed cytogenetics are associated with a poor prognosis in a population-based series of acute myeloid leukaemia
- 2015
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In: European Journal of Haematology. - Hoboken, USA : Wiley-Blackwell. - 0902-4441 .- 1600-0609. ; 94:5, s. 419-423
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Journal article (peer-reviewed)abstract
- Unsuccessful cytogenetics (UC) in patients with acute myeloid leukaemia (AML) treated on different SWOG trials was recently reported to be associated with increased age and dismal outcome. To ascertain whether this holds true also in unselected patients with AML, we retrieved all cytogenetic reports in cases from the population-based Swedish AML Registry. Between 1997 and 2006, 1737 patients below 80 yr of age without myelosarcoma or acute promyelocytic leukaemia received intensive treatment. The frequencies of UC and unperformed cytogenetics (UPC) were 2.1% and 20%, respectively. The early death rates differed between the cytogenetic subgroups (P = 0.006) with the highest rates in patients with UC (14%) and UPC (12%) followed by high-risk (HR) AML, intermediate risk (IR) and standard risk (SR) cases successfully karyotyped (8.6%, 5.9%, and 5.8%, respectively). The complete remission rate was lower in UC and UPC and HR compared with the other risk groups (P < 0.001). The overall five-year survival rates were 25% for UC and 22% for UPC, whereas the corresponding frequencies for SR, IR and HR AML patients without UC and UPC were 64%, 31% and 15%, respectively. In conclusion, lack of cytogenetic data translates into a poor prognosis.
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| 31. |
- Lazarevic, Vladimir
(author)
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i(17q) solely in myeloid malignancies
- 2012
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In: Atlas of Genetics and Cytogenetics in Oncology and Haematology. - 1768-3262. ; 16:7, s. 497-500
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Journal article (peer-reviewed)
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| 32. |
- Lazarevic, Vladimir, et al.
(author)
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Incidence and prognostic significance of karyotypic subgroups in older patients with acute myeloid leukemia: the Swedish population-based experience
- 2014
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In: Blood Cancer Journal. - London, United Kingdom : Nature Publishing Group: Open Access Journals - Option B / Nature Publishing Group. - 2044-5385. ; 4:e188
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Journal article (peer-reviewed)abstract
- The Swedish population-based acute myeloid leukemia registry contains data from 3251 patients (excluding acute promyelocytic leukemia) diagnosed between 1997 and 2006. Informative cytogenetic data from 1893 patients were retrospectively added, including 1054 patients aged between 60 and 79 years. Clonal abnormalities were found in 57% of the informative karyotypes. Karyotypic patterns differed by age: t(8; 21), inv(16) and t(11q23) were more common in younger patients, whereas loss of 5q, 7q and 17p, monosomal karyotype (MK) and complex karyotypes were more common in older patients. Loss of 5q, 7q and 17p often occurred together within MK. Patients with greater than= 5 chromosome abnormalities had worse overall survival than those with fewer abnormalities or normal karyotype in all age groups. Loss of 5q, 7q and/or 17p had, in contrast to MK, a further negative impact on survival. Multivariable Cox regression analyses on risk factors in patients less than80 years with cytogenetic abnormalities and intensive treatment revealed that age and performance status had the most significant impact on survival (both Pless than0.001), followed by sex (P = 0.0135) and a karyotype including - 7/del(7q) (P = 0.048).
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| 36. |
- Lazarevic, Vladimir Lj, et al.
(author)
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A novel t(2;17) in transformation of essential thrombocythemia to acute myelocytic leukemia.
- 2004
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In: Cancer Genetics and Cytogenetics. - 0165-4608 .- 1873-4456. ; 148:1, s. 77-9
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Journal article (peer-reviewed)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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| 37. |
- Lazarevic, Vladimir Lj
(author)
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Acute myeloid leukemia in patients we judge as being older and/or unfit
- 2021
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In: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 290:2, s. 279-293
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Research review (peer-reviewed)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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| 38. |
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| 39. |
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| 40. |
- Lazarevic, Vladimir Lj, et al.
(author)
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Relatively favorable outcome after allogeneic stem cell transplantation for BCR-ABL1-positive AML : A survey from the acute leukemia working party of the European Society for blood and marrow transplantation (EBMT)
- 2018
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In: American Journal of Hematology. - : Wiley. - 0361-8609 .- 1096-8652. ; 93:1, s. 31-39
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Journal article (peer-reviewed)abstract
- The aim of the study was to assess the role of allogeneic stem cell transplantation (SCT) in patients diagnosed with BCR-ABL1-positive acute myeloid leukemia (AML). Fifty-seven patients (median age, 48 years, range: 19-67) with BCR-ABL1 positive AML undergoing SCT were identified. The majority of the patients (70%) received a TKI before the transplant. At SCT 48 patients were in CR (45 in CR1), while 9 patients were transplanted in a more advanced stage of the disease. MRD was negative (BCR-ABL1/ABL<104) at time of SCT in 36.1% (14/40). After SCT, 16 (61.5%) out of 26 patients with MRD positive at transplantation reached MRD negativity. After a median follow-up of 6.3 years (0.7-14.2), NRM, RI, LFS, OS, and GRFS at 5 years were 18.1%, 37%, 44.2%, 53.8%, and 32.1%, respectively. The cumulative incidence of acute GvHD grade II-IV was 16.4%, incidence of chronic GvHD 24.9%, and of extensive cGvHD 21.4%, respectively. In patients who received SCT in CR1, 5-yr NRM, RI, LFS, OS, and GRFS were 15.9%, 36.4%, 46.5%, 59.4%, and 34.9%, respectively. Univariate analysis showed that age (<50 vs. ≥50 years) was associated with RI (5-yr: 22.7 vs. 50%), LFS (5-yr: 61.9 vs. 31.8%), and GRFS (5-yr: 52.4 vs. 18.2%), whereas MRD-negative status before SCT was associated with an improved GRFS (38.9 vs. 16.7%). We conclude that the outcome of patients <50 years of age with BCR-ABL1-positive AML receiving allogeneic SCT in CR is relatively favorable, possibly reflecting the beneficial effect of the use of TKI.
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| 41. |
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| 43. |
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| 44. |
- Lazarevic, Vladimir, et al.
(author)
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Prognostic significance of high hyperdiploid and triploid/tetraploid adult acute myeloid leukemia
- 2015
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In: American Journal of Hematology. - : WILEY-BLACKWELL. - 0361-8609 .- 1096-8652. ; 90:9, s. 800-805
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Journal article (peer-reviewed)abstract
- To ascertain the clinical implications of high hyperdiploid (HH; 49-65 chromosomes) and triploid/tetraploid (TT; greater than65 chromosomes) adult acute myeloid leukemia (AML), all such cases were retrieved from the Swedish AML Registry. Of the 3,654 cytogenetically informative cases diagnosed between January 1997 and May 2014, 68 (1.9%) were HH (n=50)/TT (n=18). Patients with HH/TT were older than those with intermediate risk (IR) AML (median 71 years vs. 67 years; P=0.042) and less often had de novo AML (63% vs. 79%; P=0.004); no such differences were observed between HH/TT and complex karyotype (CK) AML. The overall survival (OS) was similar between patients with HH/TT and CK AML (median 0.9 years vs. 0.6 years; P=0.082), whereas OS was significantly longer (median 1.6 years; P=0.028) for IR AML. The OS was shorter for cases with HH than with TT (median 0.6 years vs. 1.4 years; P=0.032) and for HH/TT AMLs with adverse abnormalities (median 0.8 years vs. 1.1 years; P=0.044). In conclusion, HH/TT AML is associated with a poor outcome, but chromosome numbers greater than65 and absence of adverse aberrations seem to translate into a more favorable prognosis. Thus, HH/TT AMLs are clinically heterogeneous and should not automatically be grouped as high risk.Am. J. Hematol. 90:800-805, 2015. (c) 2015 Wiley Periodicals, Inc.
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| 45. |
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| 46. |
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| 47. |
- Lazarevic, Vladimir, et al.
(author)
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TLE3 Is a Novel Fusion Partner of JAK2 in Myeloid/Lymphoid Neoplasm With Eosinophilia Responding to JAK2 Inhibition
- 2024
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In: Genes Chromosomes and Cancer. - 1045-2257. ; 63:8, s. 1-8
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Journal article (peer-reviewed)abstract
- Chromosomal rearrangements involving Janus kinase 2 (JAK2) are rare but recurrent findings in lymphoid or myeloid neoplasia. Detection of JAK2 fusion genes is important as patients with aberrantly activated JAK2 may benefit from treatment with tyrosine kinase inhibitors such as ruxolitinib. Here, we report a novel fusion gene between the transcriptional co-repressor-encoding gene transducin-like enhancer of split 3 (TLE3) and JAK2 in a patient initially diagnosed with chronic eosinophilic leukemia with additional mutations in PTPN11 and NRAS. The patient was successfully treated with the JAK2 inhibitor ruxolitinib for 8 months before additional somatic mutations were acquired and the disease progressed into an acute lymphoblastic T-cell leukemia/lymphoma. The present case shows similarities to previously reported cases with PCM1::JAK2 and BCR::JAK2 with regard to disease phenotype and response to ruxolitinib, and importantly, provides an example that also patients harboring other JAK2 fusion genes may benefit from treatment with JAK2 inhibitors.
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