The myelodysplastic syndromes (MDS) share their origin in the hematopoietic stem cell but have otherwise very heterogeneous biological and genetic characteristics. Clinical features are dominated by ...cytopenia and a substantial risk for progression to acute myeloid leukemia. According to the World Health Organization, MDS is defined by cytopenia, bone marrow dysplasia and certain karyotypic abnormalities. The understanding of disease pathogenesis has undergone major development with the implementation of next-generation sequencing and a closer integration of morphology, cytogenetics and molecular genetics is currently paving the way for improved classification and prognostication. True precision medicine is still in the future for MDS and the development of novel therapeutic compounds with a propensity to markedly change patients' outcome lags behind that for many other blood cancers. Treatment of higher-risk MDS is dominated by monotherapy with hypomethylating agents but novel combinations are currently being evaluated in clinical trials. Agents that stimulate erythropoiesis continue to be first-line treatment for the anemia of lower-risk MDS but luspatercept has shown promise as second-line therapy for sideroblastic MDS and lenalidomide is an established second-line treatment for del(5q) lower-risk MDS. The only potentially curative option for MDS is hematopoietic stem cell transplantation, until recently associated with a relatively high risk of transplant-related mortality and relapse. However, recent studies show increased cure rates due to better tools to target the malignant clone with less toxicity. This review provides a comprehensive overview of the current status of the clinical evaluation, biology and therapeutic interventions for this spectrum of disorders.
The myelodysplastic syndromes (MDSs) constitute a profoundly heterogeneous myeloid malignancy with a common origin in the hemopoietic stem cell compartment. Consequently, patient management and ...treatment are as heterogeneous. Decision-making includes identifying risk, symptoms, and options for an individual and conducting a risk-benefit analysis. The only potential cure is allogeneic stem cell transplantation, and albeit the fraction of patients with MDS who undergo transplant increase over time because of better management and increased donor availability, a majority are not eligible for this intervention. Current challenges encompass to decrease the relapse risk, the main cause of hematopoietic stem cell transplantation failure. Hypomethylating agents (HMAs) constitute firstline treatment for higher-risk MDSs. Combinations with other drugs as firstline treatment has, to date, not proven more efficacious than monotherapy, although combinations approved for acute myeloid leukemia, including venetoclax, are under evaluation and often used as rescue treatment. The treatment goal for lower-risk MDS is to improve cytopenia, mainly anemia, quality of life, and, possibly, overall survival. Erythropoiesis-stimulating agents (ESAs) constitute firstline treatment for anemia and have better and more durable responses if initiated before the onset of a permanent transfusion need. Treatment in case of ESA failure or ineligibility should be tailored to the main disease mechanism: immunosuppression for hypoplastic MDS without high-risk genetics, lenalidomide for low-risk del(5q) MDS, and luspatercept for MDS with ring sideroblasts. Approved therapeutic options are still scarcer for MDS than for most other hematologic malignancies. Better tools to match disease biology with treatment, that is, applied precision medicines are needed to improve patient outcome.
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IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZRSKP
Background
Many patients with myelodysplastic syndromes (MDS) need repeated red blood cell transfusions which entails a risk of immunization and antibody formation. Associations between ...alloantibodies, autoantibodies and increased transfusion requirements have been reported, but their relationship remains unclear. In this study, we analyzed factors potentially associated with red blood cell alloimmunization, as well as changes in transfusion intensity and post‐transfusion hemoglobin increments.
Methods
In a retrospective cohort study, we linked Swedish MDS patients diagnosed between 2003 and 2017 to transfusion and immunohematology data. Potentially associated factors were analyzed using Cox proportional hazards regression. The transfusion rate after detected alloimmunization was analyzed using a fixed effects Poisson regression. Post‐transfusion hemoglobin increments before and after alloimmunization were compared using a mixed effects regression.
Results
Alloantibodies following MDS diagnosis were detected in 50 out of 429 patients (11.7%). Female sex and a positive direct antiglobulin test (DAT) were independently associated with alloimmunization, with hazard ratios of 2.02 (95% confidence interval CI 1.08–3.78) and 9.72 (95% CI, 5.31–17.74), respectively. The transfusion rate following alloimmunization was increased with an incidence rate ratio of 1.33 (95% CI, 0.98–1.80) and the post‐transfusion hemoglobin increment after alloimmunization was 1.40 g/L (95% CI, 0.52–2.28) lower per red blood cell unit (p = .002) compared to before alloimmunization, in multivariable analyses.
Discussion
Alloimmunization against blood group antigens was associated with sex, DAT‐positivity, increased transfusion needs, and lower post‐transfusion hemoglobin increments. These findings warrant further investigation to evaluate the clinical significance of up‐front typing and prophylactic antigen matching in patients with MDS.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Germline RUNX1 mutations lead to familial platelet disorder with associated myeloid malignancy (FPDMM), characterized by thrombocytopenia, abnormal bleeding, and an elevated risk of developing ...myelodysplastic neoplasia (MDS) and acute myeloid leukemia (AML) at young age. However, it is not known why or how germline carriers of RUNX1 mutations have a particular propensity to develop myeloid hematologic malignancies, but the acquisition and composition of somatic mutations are believed to initiate and determine disease progression. We present a novel family pedigree that shares a common germline RUNX1
variant and exhibits a spectrum of somatic mutations and related myeloid malignancies (MM). RUNX1 mutations are associated with inferior clinical outcome; however, the proband of this family developed MDS with ring sideroblasts (MDS-RS), classified as a low-risk MDS subgroup. His relatively indolent clinical course is likely due to a specific somatic mutation in the SF3B1 gene. While the three main RUNX1 isoforms have been ascribed various roles in normal hematopoiesis, they are now being increasingly recognized as involved in myeloid disease. We investigated the RUNX1 transcript isoform patterns in the proband and his sister, who carries the same germline RUNX1
variant, and has FPDMM but no MM. We demonstrate a RUNX1a increase in MDS-RS, as previously reported in MM. Interestingly, we identify a striking unbalance of RUNX1b and -c in FPDMM. In conclusion, this report reinforces the relevance of somatic variants on the clinical phenotypic heterogeneity in families with germline RUNX1 deficiency and investigates a potential new role for RUNX1 isoform disequilibrium as a mechanism for development of MM.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Refractory anemia with ring sideroblasts (RARS) is a myelodysplastic syndrome (MDS) characterized by isolated erythroid dysplasia and 15% or more bone marrow ring sideroblasts. Ring sideroblasts are ...found also in other MDS subtypes, such as refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). A high prevalence of somatic mutations of SF3B1 was reported in these conditions. To identify mutation patterns that affect disease phenotype and clinical outcome, we performed a comprehensive mutation analysis in 293 patients with myeloid neoplasm and 1% or more ring sideroblasts. SF3B1 mutations were detected in 129 of 159 cases (81%) of RARS or RCMD-RS. Among other patients with ring sideroblasts, lower prevalence of SF3B1 mutations and higher prevalence of mutations in other splicing factor genes were observed (P < .001). In multivariable analyses, patients with SF3B1 mutations showed significantly better overall survival (hazard ratio HR, .37; P = .003) and lower cumulative incidence of disease progression (HR = 0.31; P = .018) compared with SF3B1-unmutated cases. The independent prognostic value of SF3B1 mutation was retained in MDS without excess blasts, as well as in sideroblastic categories (RARS and RCMD-RS). Among SF3B1-mutated patients, coexisting mutations in DNA methylation genes were associated with multilineage dysplasia (P = .015) but had no effect on clinical outcome. TP53 mutations were frequently detected in patients without SF3B1 mutation, and were associated with poor outcome. Thus, SF3B1 mutation identifies a distinct MDS subtype that is unlikely to develop detrimental subclonal mutations and is characterized by indolent clinical course and favorable outcome.
•In MDS with ring sideroblasts, SF3B1 mutation defines a homogeneous subgroup with isolated erythroid dysplasia and favorable prognosis.•MDS with ring sideroblasts and wild-type SF3B1 is mainly characterized by multilineage dysplasia and unfavorable prognosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The genetic architecture of cancer has been delineated through advances in high‐throughput next‐generation sequencing, where the sequential acquisition of recurrent driver mutations initially ...targeted towards normal cells ultimately leads to malignant transformation. Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematologic malignancies frequently initiated by mutations in the normal hematopoietic stem cell compartment leading to the establishment of leukemic stem cells. Although the genetic characterization of MDS and AML has led to identification of new therapeutic targets and development of new promising therapeutic strategies, disease progression, relapse, and treatment‐related mortality remain a major challenge in MDS and AML. The selective persistence of rare leukemic stem cells following therapy‐induced remission implies unique resistance mechanisms of leukemic stem cells towards conventional therapeutic strategies and that leukemic stem cells represent the cellular origin of relapse. Therefore, targeted surveillance of leukemic stem cells following therapy should, in the future, allow better prediction of relapse and disease progression, but is currently challenged by our restricted ability to distinguish leukemic stem cells from other leukemic cells and residual normal cells. To advance current and new clinical strategies for the treatment of MDS and AML, there is a need to improve our understanding and characterization of MDS and AML stem cells at the cellular, molecular, and genetic levels. Such work has already led to the identification of promising new candidate leukemic stem cell molecular targets that can now be exploited in preclinical and clinical therapeutic strategies, towards more efficient and specific elimination of leukemic stem cells.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Recently the World Health Organization (WHO), in collaboration with the European Association for Haematopathology and the Society for Hematopathology, published a revised and updated edition of the ...WHO Classification of Tumors of the Hematopoietic and Lymphoid Tissues. The 4th edition of the WHO classification incorporates new information that has emerged from scientific and clinical studies in the interval since the publication of the 3rd edition in 2001, and includes new criteria for the recognition of some previously described neoplasms as well as clarification and refinement of the defining criteria for others. It also adds entities—some defined principally by genetic features—that have only recently been characterized. In this paper, the classification of myeloid neoplasms and acute leukemia is highlighted with the aim of familiarizing hematologists, clinical scientists, and hematopathologists not only with the major changes in the classification but also with the rationale for those changes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary
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 100 000 inhabitants. IPSS‐R had a significantly better prognostic power than IPSS (P < 0·001). 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 ≤70 years. 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.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
BACKGROUND
RBC concentrates are commonly stored for up to 42 days but there has been conflicting evidence on the effect of storage duration and clinical outcomes. Most clinical studies have focused ...on possible associations between duration of storage time and risk for adverse outcomes, including mortality. Recent clinical trials did not find any such associations, but fewer studies have addressed whether storage time affects component efficacy. The main aim of this study was to determine the effect of RBC storage time on hemoglobin increment in transfused patients.
STUDY DESIGN AND METHODS
Transfusion data on a cohort of patients with myelodysplastic syndromes were linked to hemoglobin measurements taken between 2 days before and 28 days after a transfusion episode. We applied a mixed‐effect linear regression model, accounting for patient characteristics and time from transfusion to next hemoglobin measurement, to study the effect of RBC storage on the hemoglobin increment.
RESULTS
The study population consisted of 225 patients who received 6437 RBC units. Compared to units stored less than 5 days, transfusion of blood units stored 5 to 9, 10 to 19, 20 to 29, or 30 or more days resulted in hemoglobin increases that were 0.83 (95% confidence interval CI, 0.24–1.41), 0.92 (95% CI, 0.34–1.51), 1.33 (95% CI, 0.65–2.02) and 1.51 (95% CI, 0.58–2.43) g/L lower, respectively, per RBC unit. Results were consistent in sensitivity analyses.
CONCLUSIONS
Longer RBC storage was associated with a smaller increase in hemoglobin concentration after transfusion. Although statistically significant, the effect was modest, and its clinical relevance in subgroups of patients should be investigated in prospective clinical trials.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
ABSTRACT
Gene panel sequencing has become a common diagnostic tool for detecting somatically acquired mutations in myeloid neoplasms. However, many panels have restricted content, provide ...insufficient sensitivity levels, or lack clinically validated workflows. We here describe the development and validation of the Genomic Medicine Sweden myeloid gene panel (GMS‐MGP), a capture‐based 191 gene panel including mandatory genes in contemporary guidelines as well as emerging candidates. The GMS‐MGP displayed uniform coverage across all targets, including recognized difficult GC‐rich areas. The validation of 117 previously described somatic variants showed a 100% concordance with a limit‐of‐detection of a 0.5% variant allele frequency (VAF), achieved by utilizing error correction and filtering against a panel‐of‐normals. A national interlaboratory comparison investigating 56 somatic variants demonstrated highly concordant results in both detection rate and reported VAFs. In addition, prospective analysis of 323 patients analyzed with the GMS‐MGP as part of standard‐of‐care identified clinically significant genes as well as recurrent mutations in less well‐studied genes. In conclusion, the GMS‐MGP workflow supports sensitive detection of all clinically relevant genes, facilitates novel findings, and is, based on the capture‐based design, easy to update once new guidelines become available. The GMS‐MGP provides an important step toward nationally harmonized precision diagnostics of myeloid malignancies.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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