| 1. |
- Creignou, Maria, et al.
(author)
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Early transfusion patterns improve the Molecular International Prognostic Scoring System (IPSS-M) prediction in myelodysplastic syndromes
- 2024
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In: Journal of Internal Medicine. - : WILEY. - 0954-6820 .- 1365-2796.
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Journal article (peer-reviewed)abstract
- Background The Molecular International Prognostic Scoring System (IPSS-M) is the new gold standard for diagnostic outcome prediction in patients with myelodysplastic syndromes (MDS). This study was designed to assess the additive prognostic impact of dynamic transfusion parameters during early follow-up. Methods We retrieved complete transfusion data from 677 adult Swedish MDS patients included in the IPSS-M cohort. Time-dependent erythrocyte transfusion dependency (E-TD) was added to IPSS-M features and analyzed regarding overall survival and leukemic transformation (acute myeloid leukemia). A multistate Markov model was applied to assess the prognostic value of early changes in transfusion patterns. Results Specific clinical and genetic features were predicted for diagnostic and time-dependent transfusion patterns. Importantly, transfusion state both at diagnosis and within the first year strongly predicts outcomes in both lower (LR) and higher-risk (HR) MDSs. In multivariable analysis, 8-month landmark E-TD predicted shorter survival independently of IPSS-M (p < 0.001). A predictive model based on IPSS-M and 8-month landmark E-TD performed significantly better than a model including only IPSS-M. Similar trends were observed in an independent validation cohort (n = 218). Early transfusion patterns impacted both future transfusion requirements and outcomes in a multistate Markov model. Conclusion The transfusion requirement is a robust and available clinical parameter incorporating the effects of first-line management. In MDS, it provides dynamic risk information independently of diagnostic IPSS-M and, in particular, clinical guidance to LR MDS patients eligible for potentially curative therapeutic intervention.
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| 2. |
- Creignou, Maria
(author)
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Improving prognostication for patients with myelodysplastic syndromes
- 2023
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Doctoral thesis (other academic/artistic)abstract
- Background and aims: MDS constitute a heterogenous group of myeloid malignancies mainly characterized by dysfunctional hematopoiesis. Although cytopenia, dysplastic features and evidence of clonality are essential criteria for the diagnosis of all MDS, the several subtypes of the disease have a highly variable prognosis. The increasing quality and accessibility of DNA sequencing techniques have enabled huge advances for molecular characterization of the disease, and the prognostic impact of specific molecular markers in MDS is now well established. Several prognostic scoring systems have been developed during the last two decades but none of these tools accounted for the effect of molecular markers on outcome. MDS with RS is easily recognizable by the intra-cellular presence of iron-loaded mitochondria and this subtype reflects the heterogeneity of MDS. Hence, while RS are classically associated with SF3B1 mutations and an indolent disease course, RS are sometimes found in aggressive subtypes of MDS or AML. Patients and diseases change over time, and evolution patterns themselves can tell us something about disease biology and outcome. Clinicians account for these variations in practice, but current prognostic models do not. This may partly explain remaining discrepancies between observed and predicted prognosis. Hence, in this thesis we aimed to i) develop a novel prognostic score including molecular markers to refine prognosis prediction at diagnosis, ii) study the prognostic impact of combined gene mutation and gene expression in MDS with RS and iii) assess whether changes in erythrocyte (E) transfusion patterns during the early disease course can refine outcome prediction. Methods: Study I – an international cohort of 2957 patients with MDS, MDS/myeloproliferative neoplasms (MPN) were retrospectively collected. DNA sequencing with a panel of 152 genes known to be involved in myeloid malignancies was performed on all samples. Clinical data, cytogenetic and molecular features were retrieved and their association with outcomes was studied. A Cox multivariable model was used to estimate relative weights of selected explanatory variables. The score was validated on an independent cohort of 754 Japanese patients with MDS. Study II – A total of 129 patients with MDS and RS (MDSRS+) was assembled. All samples underwent DNA sequencing according to study I and thereafter RNA sequencing of CD34 sorted bone marrow mononuclear cells. Supervised/unsupervised clustering analysis and digital sorting were performed. A Cox multivariable model was used to assess association between clinical and genomic/transcriptomic patterns and outcome. Study III – a cohort of 677 Swedish patients was gathered from study I. We collected complete information on administered E-transfusions through the nationwide SCANDAT3-S database. Cox regression analyses were used to assess associations between clinical, molecular and transfusion data, and outcome. A Markov multistate model was used to assess association between changes in transfusion patterns and outcome. Results: Study I – TP53multi, MLL-PTD and FLT3 mutations were shown to be predictive of dismal outcome. In contrast, SF3B1 mutations were associated with favorable prognosis, however this effect was significantly influenced by the co-mutation patterns. A total of 22 variables (clinical, cytogenetic, and molecular markers) were used to build the IPSS-M score, each of them carrying a specific mathematic weight according to their individual impacts on endpoints. The calculation of the IPSS-M resulted in a unique score for individual patients and assigned each case to one of the 6 IPSS-M risk categories. When compared to the IPSS-R, the IPSS-M score clearly improved outcome prediction and led to the restratification of 46% of patients. The IPSS-M is validated both in MDS/MPN with WBC count below 13x109/L and in therapy related MDS (t-MDS). Study II – Most (~90%) MDSRS+ cases were found to have a mutation in SF3B1, SRSF2 or TP53multi. Overall, TP53multi and splice factors mutations were mutually exclusive, and SF3B1 and SRSF2 mutations cooccurred in only 3% of the patients. The three genetic subgroups were shown to have very different outcomes. Supervised transcriptome analysis confirmed the distinction between SF3B1-, SRSF2- and TP53multi-mutated MDS with RS. Unsupervised clustering analysis found three transcriptomic groups, each with distinct erythroid/megakaryocytic progenitor fraction, which predicted OS independently of IPSS-M. Study III – Whereas TP53multi, poor cytogenetic and higher bone marrow blasts predicted shorter time to first E-transfusion event, higher hemoglobin level and SF3B1alpha only were associated with longer time to first E-transfusion event. Next, E-transfusion state at 8 months after diagnosis was shown to be a strong predictor of OS independently of IPSS-M. Our model based on E-transfusion state at 8 months and IPSS-M (model 2) improved significantly prognostic prediction compared to IPSS-M only (model 1). Finally, a multistate model revealed that individual transfusion trajectories during the early disease course impacted both future transfusion requirement and OS. Conclusion: This thesis provides evidence that integration of genomic data to clinical characteristics improves greatly prognostication in MDS and we suggest that the novel IPSS-M prognostic score is implemented in clinical practice to provide further guidance in therapeutic decision-making. Our work also indicates that the heterogeneity of outcome in MDS cannot be explain by genetic profiling only and that studies of gene expression and integration of dynamic parameters among other techniques will contribute to a better understanding of the clinical course. In general, this thesis advocates for the need of a holistic approach of the disease to deepen our understanding of underlying mechanisms and ultimately to improve the care of patients with MDS. Enormous efforts are currently put in the field of precision medicine in cancer. Future integrative multiomics studies will hopefully improve individualized care to increase survival and quality of life of patients with MDS.
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| 4. |
- Söderlund, Stina, et al.
(author)
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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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In: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 98:1, s. 57-66
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Journal article (peer-reviewed)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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| 5. |
- Todisco, Gabriele, et al.
(author)
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Integrated Genomic and Transcriptomic Analysis Improves Disease Classification and Risk Stratification of MDS with Ring Sideroblasts
- 2023
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In: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 29:20, s. 4256-4267
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Journal article (peer-reviewed)abstract
- Purpose: Ring sideroblasts (RS) define the low-risk myelodysplastic neoplasm (MDS) subgroup with RS but may also reflect erythroid dysplasia in higher risk myeloid neoplasm. The benign behavior of MDS with RS (MDSRSþ) is limited to SF3B1-mutated cases without additional high-risk genetic events, but one third of MDSRSþ carry no SF3B1 mutation, suggesting that different molecular mechanisms may underlie RS formation. We integrated genomic and transcriptomic analyses to evaluate whether transcriptome profiles may improve current risk stratification. Experimental Design: We studied a prospective cohort of MDSRSþ patients irrespective of World Health Organization (WHO) class with regard to somatic mutations, copy-number alterations, and bone marrow CD34þ cell transcriptomes to assess whether transcriptome profiles add to prognostication and provide input on disease classification. Results: SF3B1, SRSF2, or TP53 multihit mutations were found in 89% of MDSRSþ cases, and each mutation category was associated with distinct clinical outcome, gene expression, and alternative splicing profiles. Unsupervised clustering analysis identified three clusters with distinct hemopoietic stem and progenitor (HSPC) composition, which only partially overlapped with mutation groups. IPSS-M and the transcriptome-defined proportion of megakaryocyte/erythroid progenitors (MEP) independently predicted survival in multivariable analysis. Conclusions: These results provide essential input on the molecular basis of SF3B1-unmutated MDSRSþ and propose HSPC quantification as a prognostic marker in myeloid neoplasms with RS.
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| 6. |
- Wedge, Eileen, et al.
(author)
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Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Myelomonocytic Leukemia : Clinical and Molecular Genetic Prognostic Factors in a Nordic Population
- 2021
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In: Transplantation and Cellular Therapy. - : Elsevier. - 2666-6375 .- 2666-6367. ; 27:12, s. 991.e1-991.e9
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Journal article (peer-reviewed)abstract
- Chronic myelomonocytic leukemia (CMML) is an aggressive disease in which survival after allogeneic hematopoietic stem cell transplantation (HCT) remains relatively poor. An assessment of prognostic factors is an important part of treatment decision making and has the potential to be greatly improved by the inclusion of molecular genetics. However, there is a significant knowledge gap in the interpretation of mutational patterns. This study aimed to describe outcomes of allogeneic HCT in patients with CMML in relation to clinical and molecular genetic risk factors. This retrospective study included 64 patients with CMML who underwent allogeneic HCT between 2008 and 2018, with a median follow-up of 5.4 years. Next-generation sequencing using targeted myeloid panels was carried out on saved material from 51 patients from the time of transplantation. Kaplan-Meier and Cox regression were used for analysis of overall survival (OS), and cumulative incidence with competing risks and Fine and Gray models were used for analysis of relapse and nonrelapse mortality (NRM). Mutations were detected in 48 patients (94%), indicating high levels of minimal residual disease (MRD) positivity at transplantation, even among those in complete remission (CR) (n = 14), 86% of whom had detectable mutations. The most frequently mutated genes were ASXL1 (37%), TET2 (37%), RUNX1 (33%), SRSF2 (26%), and NRAS (20%). Risk stratification using the CMML-specific Prognostic Scoring System molecular score (CPSS-Mol) resulted in 45% of patients moving to a higher risk-group compared with risk stratification using the CPSS. High leucocyte count (>= 13 x 10(9)/L), transfusion requirement, and previous intensive chemotherapy were associated with higher incidence of relapse. Being in CR was not linked to better outcomes. Neither ASXL1 nor RUNX1 mutation was associated with a difference in OS, relapse, or NRM, despite being high risk in the nontransplantation setting. TET2 mutations were associated with a significantly higher 3-year OS (73% versus 40%; P =.039). Achieving MRD-negative CR was rare in this CMML cohort, which may explain why we did not observe better outcomes for those in CR. This merits further investigation. Our analyses suggest that the negative impact of ASXL1 and RUNX1 mutations can be overcome by allogeneic HCT; however, risk stratification is complex in CMML and requires larger cohorts and multivariate models, presenting an ongoing challenge in this rare disease.
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