| 1. |
- Österroos, Albin, et al.
(författare)
-
A risk score based on real-world data to predict early death in acute promyelocytic leukemia
- 2022
-
Ingår i: Haematologica. - : Ferrata Storti Foundation. - 0390-6078 .- 1592-8721. ; 107:7, s. 1528-1537
-
Tidskriftsartikel (refereegranskat)abstract
- With increasingly effective treatments, early death (ED) has become the predominant reason for therapeutic failure in patients with acute promyelocytic leukemia (APL). To better prevent ED, patients with high-risk of ED must be identified. Our aim was to develop a score that predicts the risk of ED in a real-life setting. We used APL patients in the population based Swedish AML Registry (n=301) and a Portuguese hospital-based registry (n=129) as training and validation cohorts, respectively. The cohorts were comparable with respect to age (median, 54 and 53 years) and ED rate (19.6% and 18.6%). The score was developed by logistic regression analyses, risk-per-quantile assessment and scoring based on ridge regression coefficients from multivariable penalized logistic regression analysis. White blood cell count, platelet count and age were selected by this approach as the most significant variables for predicting ED. The score identified low-, high-and very high-risk patients with ED risks of 4.8%, 20.2% and 50.9% respectively in the training cohort and with 6.7%, 25.0% and 36.0% as corresponding values for the validation cohort. The score identified an increased risk of ED already at sub-normal and normal white blood cell counts and, consequently, it was better at predicting ED risk than the Sanz score (AUROC 0.77 vs. 0.64). In summary, we here present an externally validated and population-based risk score to predict ED risk in a real-world setting, identifying patients with the most urgent need of aggressive ED prevention. The results also suggest that increased vigilance for ED is already necessary at sub-normal/normal white blood cell counts.
|
|
| 2. |
- Berggren, Daniel Moreno, et al.
(författare)
-
Prognostic scoring systems for myelodysplastic syndromes (MDS) in a population-based setting : a report from the Swedish MDS register
- 2018
-
Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 181:5, s. 614-627
-
Tidskriftsartikel (refereegranskat)abstract
- The myelodysplastic syndromes (MDS) have highly variable outcomes and prognostic scoring systems are important tools for risk assessment and to guide therapeutic decisions. However, few population-based studies have compared the value of the different scoring systems. With data from the nationwide Swedish population-based MDS register we validated the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R) and the World Health Organization (WHO) Classification-based Prognostic Scoring System (WPSS). We also present population-based data on incidence, clinical characteristics including detailed cytogenetics and outcome from the register. The study encompassed 1329 patients reported to the register between 2009 and 2013, 14% of these had therapy-related MDS (t-MDS). Based on the MDS register, the yearly crude incidence of MDS in Sweden was 2.9 per 100000 inhabitants. IPSS-R had a significantly better prognostic power than IPSS (P < 0001). There was a trend for better prognostic power of IPSS-R compared to WPSS (P=0.05) and for WPSS compared to IPSS (P=0.07). IPSS-R was superior to both IPSS and WPSS for patients aged <= 70years. Patients with t-MDS had a worse outcome compared to de novo MDS (d-MDS), however, the validity of the prognostic scoring systems was comparable for d-MDS and t-MDS. In conclusion, population-based studies are important to validate prognostic scores in a real-world' setting. In our nationwide cohort, the IPSS-R showed the best predictive power.
|
|
| 3. |
- Dolinska, Monika, et al.
(författare)
-
Characterization of Bone Marrow Niche in Chronic Myeloid Leukemia Patients Identifies CXCL14 as a New Therapeutic Option
- 2023
-
Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 142:1, s. 73-89
-
Tidskriftsartikel (refereegranskat)abstract
- Although tyrosine kinase inhibitors (TKIs) are effective in treating chronic myeloid leukemia (CML), they often fail to eradicate the leukemia-initiating stem cells (LSCs), causing disease persistence and relapse. Evidence indicates that LSC persistence may be because of bone marrow (BM) niche protection; however, little is known about the underlying mechanisms. Herein, we molecularly and functionally characterize BM niches in patients with CML at diagnosis and reveal the altered niche composition and function in these patients. Long-term culture initiating cell assay showed that the mesenchymal stem cells from patients with CML displayed an enhanced supporting capacity for normal and CML BM CD34+CD38- cells. Molecularly, RNA sequencing detected dysregulated cytokine and growth factor expression in the BM cellular niches of patients with CML. Among them, CXCL14 was lost in the BM cellular niches in contrast to its expression in healthy BM. Restoring CXCL14 significantly inhibited CML LSC maintenance and enhanced their response to imatinib in vitro, and CML engraftment in vivo in NSG-SGM3 mice. Importantly, CXCL14 treatment dramatically inhibited CML engraftment in patient-derived xenografted NSG-SGM3 mice, even to a greater degree than imatinib, and this inhibition persisted in patients with suboptimal TKI response. Mechanistically, CXCL14 upregulated inflammatory cytokine signaling but downregulated mTOR signaling and oxidative phosphorylation in CML LSCs. Together, we have discovered a suppressive role of CXCL14 in CML LSC growth. CXCL14 might offer a treatment option targeting CML LSCs.
|
|
| 4. |
- Dolinska, Monika, et al.
(författare)
-
Characterization of the bone marrow niche in patients with chronic myeloid leukemia identifies CXCL14 as a new therapeutic option
- 2023
-
Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 142:1, s. 73-89
-
Tidskriftsartikel (refereegranskat)abstract
- Although tyrosine kinase inhibitors (TKIs) are effective in treating chronic myeloid leukemia (CML), they often fail to eradicate the leukemia-initiating stem cells (LSCs), causing disease persistence and relapse. Evidence indicates that LSC persistence may be because of bone marrow (BM) niche protection; however, little is known about the underlying mechanisms. Herein, we molecularly and functionally characterize BM niches in patients with CML at diagnosis and reveal the altered niche composition and function in these patients. Long -term culture initiating cell assay showed that the mesenchymal stem cells from patients with CML displayed an enhanced supporting capacity for normal and CML BM CD34+CD38- cells. Molecularly, RNA sequencing detected dysregulated cytokine and growth factor expression in the BM cellular niches of patients with CML. Among them, CXCL14 was lost in the BM cellular niches in contrast to its expression in healthy BM. Restoring CXCL14 significantly inhibited CML LSC maintenance and enhanced their response to imatinib in vitro, and CML engraftment in vivo in NSG-SGM3 mice. Importantly, CXCL14 treatment dramatically inhibited CML engraftment in patient-derived xenografted NSG-SGM3 mice, even to a greater degree than imatinib, and this inhibition persisted in patients with suboptimal TKI response. Mechanistically, CXCL14 upregulated inflammatory cytokine signaling but downregulated mTOR signaling and oxidative phosphorylation in CML LSCs. Together, we have discovered a suppressive role of CXCL14 in CML LSC growth. CXCL14 might offer a treatment option targeting CML LSCs.
|
|
| 5. |
- Jädersten, Martin, et al.
(författare)
-
Erythropoietin and granulocyte-colony stimulating factor treatment associated with improved survival in myelodysplastic syndrome
- 2008
-
Ingår i: Journal of Clinical Oncology. - New York, N.Y. : Grune & Stratton. - 0732-183X .- 1527-7755. ; 26:21, s. 3607-3613
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose To assess the effect of erythropoietin (EPO) plus granulocyte-colony stimulating factor (G-CSF) treatment on survival and leukemic transformation in myelodysplastic syndrome (MDS).Patients and Methods We compared the long-term outcome of patients with MDS treated with EPO plus G-CSF (n = 121) with untreated patients (n = 237) with MDS using multivariate Cox regression with delayed entry, for the first time adjusting for all major prognostic variables (WHO classification, karyotype, cytopenias, level of transfusion-need, age, and sex).Results The erythroid response rate to EPO plus G-CSF was 39%, and the median response duration 23 months (range, 3 to 116+). In the multivariate analysis, treatment was associated with improved overall survival (hazard ratio, 0.61; 95% CI, 0.44 to 0.83; P = .002). Interestingly, this positive association was primarily observed in patients requiring fewer than 2 units of RBCs per month. Treatment was not linked to the rate of acute myeloid leukemia in any defined subgroup, including patients with an increase of marrow blasts or an unfavorable karyotype.Conclusion The inherent risk of leukemic evolution in MDS makes the current investigation highly relevant, in light of the recent reports of potential negative effects of EPO treatment on outcome in patients with cancer. We conclude that treatment of anemia in MDS with EPO plus G-CSF may have a positive impact on outcome in patients with no or low transfusion need, while not affecting the risk of leukemic transformation.
|
|
| 6. |
- Jädersten, Martin
(författare)
-
Studies of anemia in the myelodysplastic syndromes
- 2008
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The myelodysplastic syndromes (MDS) constitute a heterogeneous group of malignant bone marrow disorders, characterized by chronic anemia and increased risk of transformation to acute myeloid leukemia (AML). The first line therapy of anemia in MDS is erythropoietin (EPO) with or without granulocyte colony-stimulating factor (G-CSF). Recently, reports about adverse effects of EPO on survival in patients with solid tumors have resulted in questions about its role in MDS. Lenalidomide has a potent effect in 5q- syndrome, however, its mechanisms of action and long-term safety have not yet been studied sufficiently. Aims: To assess the long-term efficacy and effects on outcome of treatment for anemia in MDS with EPO and G-CSF. To study the in vitro effects of lenalidomide on bone marrow progenitor cells from patients with low-risk MDS and del(5q). To investigate the presence of pre-treatment molecular lesions in patients with del(5q) low-risk MDS treated with lenalidomide, who subsequently underwent disease transformation. Methods and results: We conducted a long-term follow-up of three studies of EPO and G-CSF treatment of anemia in MDS. The overall erythroid response rate was 39%, and the median response duration 23 months (range 3 to 116+ months). Patients with low-risk disease as well as complete erythroid responders had longer response duration. Most relapses were due to unknown factors; only 18% were attributable to a significant blast progression. Next, we evaluated the effect of treatment on survival and risk of leukemic evolution by comparing the treated cohort with untreated patients from two large datasets. In a multivariate analysis, we demonstrated that treatment with EPO and G-CSF was associated with improved survival in patients requiring <2 units of packed red blood cells (RBC) per month (hazard ratio [HR] 0.44; 95% confidence interval [CI], 0.29 to 0.66; P < 0.001). There was no association with the risk of AML evolution (HR, 0.89; 95%CI, 0.52 to 1.52; P = 0.66). We also studied the effects of lenalidomide on immature hematopoietic progenitor cells from patients with MDS and del(5q) in an erythroblast culture model. Lenalidomide inhibited the growth of malignant cells, while not affecting normal cells. Furthermore, lenalidomide affected gene expression of del(5q) progenitors, and up-regulated the tumor suppressor gene SPARC, located within the commonly deleted segment at 5q31. Finally, we describe two patients with 5q- syndrome, who initially responded well to lenalidomide but after two years unexpectedly developed progressive disease. Before treatment, we were able to demonstrate subclones of bone marrow cells with abnormal cytoplasmic nucleophosmin (NPMc+) and overexpression of p53, generally associated with high-risk MDS and AML. Both the NPMc+ and the p53 expressing subclones expanded at disease progression, and sequencing of TP53 confirmed a pre-treatment heterozygous mutation and a homozygous mutation at disease transformation. Conclusions: Treatment with EPO and G-CSF in MDS (a) leads to long-term responses, (b) is associated with improved survival in patients requiring <2 units of RBC per month, and (c) does not alter the risk of AML evolution. Lenalidomide specifically inhibits the malignant bone marrow progenitors from patients with MDS and del(5q), and up-regulates the tumor suppressor gene SPARC which may be an important aspect of lenalidomide s mechanisms of action of as well as of disease pathogenesis. Patients with 5q- syndrome responding to lenalidomide and subsequently undergoing disease progression may already before treatment have molecular lesions affecting the genomic stability. The presence of such abnormalities could play a role in a future pre-treatment risk-stratification.
|
|
| 7. |
- Larfors, Gunnar, et al.
(författare)
-
Income, education and their impact on treatments and survival in patients with myelodysplastic syndromes
- 2021
-
Ingår i: European Journal of Haematology. - : Munksgaard Forlag. - 0902-4441 .- 1600-0609. ; 107:2, s. 219-228
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: To assess whether socioeconomic indices such as income and educational level can explain part of the variation in survival among patients with myelodysplastic syndromes, and further to assess whether these factors influence care and treatment decisions.Methods: Population-based cohort study on 2945 Swedish patients diagnosed between 2009 and 2018 and included in the Swedish MDS Register. Relative mortality was assessed by Cox regression, whereas treatment differences were assessed by Poisson regression. Regarding mortality, patients were also compared to a matched comparison group from the general population.Results: Mortality was 50% higher among patients in the lowest income category compared to the highest and 40% higher in patients with mandatory school education only compared to those with college or university education. Treatment with hypomethylating agents and allogeneic stem cell transplantation, as well as investigation with cytogenetic diagnostics were also linked to income and education. The findings were not explained by differences in risk class or comorbidity at the time of diagnosis.Conclusions: Income and education are linked to survival among patients with myelodysplastic syndromes. Socioeconomic status also seems to influence treatment intensity as patients with less income and education to a lesser degree receive hypomethylating agents and transplants.
|
|
| 8. |
- Moreno Berggren, Daniel
(författare)
-
Population-based studies in Myelodysplastic syndromes : Prognostic scores, socioeconomic status, and therapy-related disease
- 2023
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to expand the epidemiological knowledge of the haematological malignancy MDS and the related condition chronic myelomonocytic leukaemia (CMML). Using nationwide registers, the papers in this thesis address aspects of prognostication, comorbidity, socioeconomic status, and therapy-related disease, using a population-based approach.In paper I we validated the prognostic scoring systems WPSS, IPSS, and IPSS-R in a cohort of 1329 MDS patients. IPSS-R was the most effective scoring system, with the highest C-index of 0.74. The scoring systems were equally effective for therapy-related MDS (t-MDS) as they were for de novo MDS. In paper II we validated the scoring systems, IPSS-R, CPSS, MDAPS, and Mayo score and the comorbidity indices CCI, HCT-CI, and MDS-CI in a cohort of 337 patients with CMML. We concluded that CPSS is the most powerful scoring system. Among comorbidity indices, the CCI gave the most prognostic information. There was a strikingly high prevalence of autoimmune conditions affecting 25% of patients. In paper III we studied the effect of socioeconomic status in a cohort of 2945 patients with MDS. When adjusting for known prognostic factors, mortality was 50% higher in patients with the lowest income compared to those with the highest income and 40% higher among patients with the shortest education compared to those with the longest. Further, a lower socioeconomic status was associated with a reduced probability of receiving effective treatment and with a lower probability of a cytogenetic evaluation at diagnosis. In paper IV we studied t-MDS in a cohort of 2705 patients with MDS, of whom 16% had t-MDS. Patients with t-MDS had a shorter median survival as compared to de novo MDS (15.8 months versus 31.1 months). Previous treatment with either chemotherapy alone or in combination with radiation was associated with a shorter survival than treatment with radiation only. Having a non-malignant disease or a solid tumour as a primary disease was associated with a longer survival, compared with those with a haematological malignancy. IPSS-R and the WHO classification were effective in predicting survival in most subgroups of t-MDS. The t-MDS subgroup treated with radiation only was similar to patients with de novo MDS and should be regarded as having de novo MDS regarding prognostication and treatment.In summary, the findings in this thesis provide evidence for how to improve prognostication and expand knowledge on the patient and disease-specific characteristics leading to the diverse outcomes in MDS and CMML.
|
|
| 9. |
- Moreno Berggren, Daniel, et al.
(författare)
-
Prognostic scoring systems and comorbidities in chronic myelomonocytic leukaemia : a nationwide population-based study
- 2021
-
Ingår i: British Journal of Haematology. - : John Wiley & Sons. - 0007-1048 .- 1365-2141. ; 192:3, s. 474-483
-
Tidskriftsartikel (refereegranskat)abstract
- Outcomes in chronic myelomonocytic leukaemia (CMML) are highly variable and may be affected by comorbidity. Therefore, prognostic models and comorbidity indices are important tools to estimate survival and to guide clinicians in individualising treatment. In this nationwide population-based study, we assess comorbidities and for the first time validate comorbidity indices in CMML. We also compare the prognostic power of: the revised International Prognostic Scoring System (IPSS-R), CMML-specific prognostic scoring system (CPSS), MD Anderson Prognostic Scoring System (MDAPS) and Mayo score. In this cohort of 337 patients with CMML, diagnosed between 2009 and 2015, the median overall survival was 21 center dot 3 months. Autoimmune conditions were present in 25% of the patients, with polymyalgia rheumatica and Hashimoto's thyroiditis being most common. Of the tested comorbidity indices: the Charlson Comorbidity Index (CCI), Haematopoietic cell transplantation-specific Comorbidity Index (HCT-CI) and Myelodysplastic Syndrome-Specific Comorbidity Index (MDS-CI), CCI had the highest C-index (0 center dot 62) and was the only comorbidity index independently associated with survival in multivariable analyses. When comparing the prognostic power of the scoring systems, the CPSS had the highest C-index (0 center dot 69). In conclusion, using 'real-world' data we found that the CCI and CPSS have the best prognostic power and that autoimmune conditions are overrepresented in CMML.
|
|
| 10. |
- Moreno Berggren, Daniel, et al.
(författare)
-
Therapy-related MDS dissected based on primary disease and treatment-a nationwide perspective
- 2023
-
Ingår i: Leukemia. - : Springer. - 0887-6924 .- 1476-5551. ; 37:5, s. 1103-1112
-
Tidskriftsartikel (refereegranskat)abstract
- In this population-based study, we aimed to characterize and compare subgroups of therapy-related Myelodysplastic syndromes (t-MDS) and define the implications of type of previous treatment and primary disease. We combined data from MDS patients, diagnosed between 2009 and 2017 (n = 2705), in the nationwide Swedish MDS register, with several health registers. Furthermore, using matched population controls, we investigated the prevalence of antecedent malignancies in MDS patients in comparison with the general population. This first ever nationwide study on t-MDS confirms a shorter median survival for t-MDS compared to de novo MDS (15.8 months vs 31.1 months, p < 0.001). T-MDS patients previously treated with radiation only had disease characteristics with a striking resemblance to de novo-MDS, in sharp contrast to patients treated with chemotherapy who had a significantly higher risk profile. IPSS-R and the WHO classification differentiated t-MDS into different risk groups. As compared with controls, MDS patients had a six-fold increased prevalence of a previous hematological malignancy but only a 34% increased prevalence of a previous solid tumor. T-MDS patients with a previous hematological malignancy had a dismal prognosis, due both to mortality related to their primary disease and to high-risk MDS.
|
|
