Prevalence and risk factors predisposing low bone mineral density in patients with thalassemia.

Background: A common complication of thalassemia is secondary osteoporosis. This study aimed to assess the prevalence and factors associated with low BMD in thalassemic patients. Method: This is a cross-sectional study. Eligible patients were males aged within 18-49 years or premenopausal women diagnosed with thalassemia in Chiang Mai University Hospital between July 2021 and July 2022. The diagnosis of low BMD by dual-energy x-ray absorptiometry (DXA) was defined as a Z-score of -2.0 SD or lower in either the lumbar spine or femoral neck. Clinical factors associated with low BMD were analyzed using a logistic regression model. Results: Prevalence of low BMD was 62.4% from 210 patients with a mean age of 29.7 ± 7.6 years. The predominant clinical characteristics of low BMD thalassemia patients were being female, transfusion-dependent (TDT) and a history of splenectomy. From multivariable analysis, the independent variables associated with low BMD were transfusion dependency (odds ratio, OR 2.36; 95%CI 1.28 to 4.38; p=0.006) and body mass index (BMI) (OR 0.71; 95%CI 0.61 to 0.82; p<0.001). Among patients with low BMD, we observed a correlation between a Z-score with low IGF-1 levels (ß=-0.42; 95% CI -0.83 to -0.01; p=0.040), serum phosphate levels (ß=0.40; 95% CI 0.07 to 0.73; p=0.016) and hypogonadism (ß=-0.48, 95% CI -0.91 to -0.04, p=0.031). Conclusion: This study found a prevalence of low BMD in 62.4% of subjects. Factors associated with low BMD were TDT and BMI. Within the low BMD subgroup, hypogonadism, serum phosphate and low serum IGF-1 levels were associated with a lower Z-score.

Usefulness of Genetic Aberration and Shorter Telomere Length in Myelodysplastic Syndrome: A Pilot Study.

OBJECTIVE: We aimed to evaluate the clinical usefulness of genetic aberration and shorter telomere length (TL) in individuals with myelodysplastic syndrome (MDS). METHODS: A targeted sequencing panel with 49 genes and TL measurement by quantitative real-time polymerase chain reaction were performed for 46 subjects. RESULTS: According to the revised International Prognostic Scoring System (IPSS-R) subtypes, the mutation frequency was 33.3%, 57.9%, and 100% in the very low/low, intermediate, and very high/high risk groups, respectively. A shorter telomere was detected in 43.5%. We defined group 1 as IPSS-R-high or -very high risk, group 2 as having 1 or more genetic aberrations, group 3 as having a shorter TL, and group 4 as having a longer TL than the age-matched reference. Group 1 and group 2 showed an adverse prognosis. The TL was not strongly correlated with MDS prognosis. However, it may be related to a poor long-term prognosis. CONCLUSION: Genetic variation and shorter TL may be helpful in reclassifying non-high-risk groups.

Red blood cell transfusion burden in myelodysplastic syndromes (MDS) with ring Sideroblasts (RS): A retrospective multicenter study by the Groupe Francophone des Myélodysplasies (GFM).

BACKGROUND: MDS-RS patients are characterized by chronic anemia and a low risk of Acute Myeloid Leukemia (AML) progression and they generally become Red Blood Cell (RBC) transfusion dependent (TD). STUDY DESIGN AND METHODS: We performed a retrospective "real-life" observational study of 6 months in 100 MDS-RS TD patients, recruited in 12 French centers, to describe transfusion characteristics, and evaluate the frequency and causes of hospitalizations, health costs, and morbidity, associated with transfusion dependency, in a French population of RBC transfusion-dependent MDS-RS patients. RESULTS: 79% of the patients had high transfusion burden (HTB) and 21% low transfusion burden (LTB). HTB patients had a longer disease duration (6 vs. 3.7 years, p = 0.0078), more frequent iron chelation (82% vs. 50%, p = 0.0052) and higher serum ferritin (p = 0.03). During the 6-month study period, 22% of the patients required inpatient hospitalization, 36% of them for symptomatic anemia requiring emergency RBC transfusion. The 6-month median transfusion costs, including the cost of the day care facility, transportation to and from the hospital, iron chelation, and lab tests, was 16,188€/patient. DISCUSSION: MDS-RS represents the archetypal type of chronically transfused lower-risk MDS. Most of those patients have a high transfusion burden and thus frequently need visits to the hospital's day care facility, and frequent hospitalizations, with an overall high median treatment cost. Those costs should be compared with costs of new treatments potentially able to avoid RBC transfusion dependence and to reduce the complications of chronic anemia in MDS-RS patients.

Clinical practice for outpatients that are chronically red cell dependent: A survey in the Netherlands.

BACKGROUND AND OBJECTIVES: Limited data are available to guide physicians on how to determine the red blood cell (RBC) transfusion regimen in chronically transfusion-dependent patients. The lack of clarity on thresholds and targets to be used for transfusion could easily result in either under or over transfusion in these patients. The aim of our survey is to investigate (1) transfusion thresholds; (2) number of RBC units given per transfusion episode; (3) interval between transfusions and (4) patient factors, like decreased cardiac function modulating the former. MATERIALS AND METHODS: We sent a web-based 44-question survey to members of the Dutch Haematology Association. RESULTS: Fifty physicians responded between June and October 2020 (response rate 30%), well-distributed between community and academic hospitals. A wide variation in transfusion strategies was reported: Most patients have transfused 1-2 RBC units (range: 0-3 units) every 2-4 weeks (range: 1-12 weeks) with a median threshold of 8.0 g/dl ranging from 6.4 to 9.6 g/dl. Patient-specific clinical factors that are most frequently reported to influence the transfusion strategy are angina pectoris, cardiac failure and dyspnoea, softer parameters that are of influence are the quality of life and self-sustainability. CONCLUSION: The results of this survey indicate a broad variation in RBC transfusion strategies in Dutch patients with chronic transfusion dependency. While the current variation in transfusion strategies may be unavoidable in an individualized approach, randomized trials and better defined usable parameters to evaluate the effect of transfusion strategies are required to reach a consensus on how to determine the transfusion strategy.

Advances in Treatment of Transfusion-dependent Lower-risk Myelodysplastic Syndromes / 肿瘤防治研究

At present, the patients with transfusion-dependent lower-risk myelodysplastic syndromes (MDS) have limited treatment options when erythropoiesis-stimulating agent is ineffective or relapsed. With more understanding of the pathological and molecular genetics characteristics of MDS, the development of precise medical treatment of MDS has been promoted. Small-molecule inhibitors, such as transforming growth factor β inhibiter, telomerase inhibiter and hypoxia-inducible factor prolyl hydroxylase inhibitor, provide novel therapeutic strategies for patients. This article reviews the treatment of transfusion-dependent lower-risk MDS patients and discusses the latest clinical research and development of novel targeted agents.

Improving Prognostic Modeling in Myelodysplastic Syndromes.

Myelodysplastic syndromes (MDSs) are a heterogeneous group of disorders characterized by the accumulation of complex genetic alterations that drive disease pathogenesis and outcome. Several prognostic models have been developed over the last two decades to risk stratify patients with MDS. These models mainly used clinical variables including blast percentage, cytopenias, cytogenetics, transfusion dependency, and age. Recently, somatic mutations in specific genes have been shown to impact overall survival in MDS and can be incorporated into established prognostic models to improve their predictive abilities. Here, we review the advantages and disadvantages of established prognostic models in MDS and the impact of emerging data regarding the incorporation of somatic mutations in risk stratification.

Effect of Red Blood Cell Transfusion Dependence on the Natural History of Myeloproliferative Neoplasm-Associated Myelofibrosis.

BACKGROUND: There are 2 widely used criteria for red blood cell (RBC) transfusion dependence in persons with myeloproliferative neoplasm (MPN)-associated myelofibrosis: (1) the International Working Group-Myelofibrosis Research and Therapy (IWG-MRT) criteria (receipt of 2 U RBC in the preceding month); and (2) the Rand-Delphi definition (2 U RBC per month averaged over 3 months). We studied effect of these criteria on survival and risk of leukemic transformation in 259 subjects with MPN-associated myelofibrosis. PATIENTS AND METHODS: On the basis of hemoglobin (Hb) and transfusion history, subjects were assigned to 1 of the 4 cohorts: (1) Hb ≥ 100 g/L (n = 136; 52%) and no RBC transfusions in the preceding 4 months; (2) Hb < 100 g/L, and no RBC transfusions in the preceding 4 months (n = 56; 22%); (3) subjects who met IWG-MRT criteria, but not the Rand-Delphi criteria for RBC transfusion dependence (n = 34; 13%); and (4) subjects who met the Rand-Delphi criteria for RBC transfusion dependence (n = 33; 13%). RESULTS: Three-year probability of survival among the 4 cohorts was 81% (95% confidence interval [CI], 71-87), 55% (95% CI, 36-71), 52% (95% CI, 31-69), and 47% (95% CI, 24-67), respectively (P = .0005). There was no significant difference in baseline characteristics or survival between cohorts 3 and 4 and they were combined for subsequent analyses. In multivariate analyses, subjects who met either definition of RBC transfusion dependence had significantly worse survival (hazard ratio, 2.61; 95% CI, 1.38-4.96; P = .01). CONCLUSION: RBC transfusion dependence is associated with worse survival irrespective of definition of transfusion dependence. No effect of anemia or RBC transfusion dependence on leukemic transformation was observed.

Transfusion dependency at diagnosis and transfusion intensity during initial chemotherapy are associated with poorer outcomes in adult acute myeloid leukemia.

Blood transfusions can modify host immunity and clinical outcomes in hematological malignancies. One thousand sixty-seven patients with acute myeloid leukemia (AML) were studied for their transfusion dependency at initial presentation and transfusion frequency during induction chemotherapy. Three hundred five patients (29 %) showed initial dependence to red blood cell (RBC) transfusion and 109 (10 %) to platelet transfusion. Transfusion dependency at presentation was associated with a poorer prognosis. Both initial RBC and platelet transfusion needs were associated with lower response rates (P = 0.04 and P = 0.03). Median overall survival (OS) was 10.8 months for patients with RBC need vs 18.8 months for the other patients (P = 0.02) and 6.8 months for patients with platelet transfusion need vs 13.6 months for the others (P = 0.01). Similarly, transfusion intensity during induction therapy influenced negatively treatment outcome. Median transfusion burden per week was 2.5 (range 0-25.7) RBC units and 1.6 (range 0-15.7) platelet concentrates (PCs). Both high RBC and PC transfusion intensities were associated with lower response rates (P = 0.003 and P < 0.0001). Median OS was 9.08 months for patients with RBC transfusions >3/week vs 18.29 months for those with RBC transfusions ≤3/week (P = 0.0003) and 10.75 months for patients with PC transfusions >2/week vs 19.96 months for those with PC ≤2/week (P = 0.0003). RBC and platelet transfusion intensities during induction therapy remained of prognostic value in multivariate analysis. Transfusion need at presentation and the frequency of transfusions during induction chemotherapy appear as strong prognostic factors.

Adequate iron chelation therapy for at least six months improves survival in transfusion-dependent patients with lower risk myelodysplastic syndromes.

BACKGROUND: Most patients with myelodysplastic syndromes (MDS) require transfusions at the risk of iron overload and associated organ damage, and death. Emerging evidence indicates that iron chelation therapy (ICT) could reduce mortality and improve survival in transfusion-dependent MDS patients, especially those classified as International Prognostic Scoring System (IPSS) Low or Intermediate-1 (Low/Int-1). METHODS: Follow-up of a retrospective study. Sample included 127 Low/Int-1 MDS patients from 28 centers in Belgium. Statistical analysis stratified by duration (≥6 versus <6 months) and quality of chelation (adequate versus weak). RESULTS: Crude chelation rate was 63% but 88% among patients with serum ferritin ≥1000 µg/L. Of the 80 chelated patients, 70% were chelated adequately mainly with deferasirox (26%) or deferasirox following deferoxamine (39%). Mortality was 70% among non-chelated, 40% among chelated, 32% among patients chelated ≥6 m, and 30% among patients chelated adequately; with a trend toward reduced cardiac mortality in chelated patients. Overall, median overall survival (OS) was 10.2 years for chelated and 3.1 years for non-chelated patients (p<0.001). For patients chelated ≥6 m or patients classified as adequately chelated, median OS was 10.5 years. Mortality increased as a function of average monthly transfusion intensity (HR=1.08, p=0.04) but was lower in patients receiving adequate chelation or chelation ≥6 m (HR=0.24, p<0.001). CONCLUSION: Six or more months of adequate ICT is associated with markedly better overall survival. This suggests a possible survival benefit of ICT in transfusion-dependent patients with lower-risk MDS.

The spectrum of non-classical Diamond-Blackfan anemia: a case of late beginning transfusion dependency associated to a new RPL5 mutation.

Diamond Blackfan anemia typically presents in infants and is often associated with many kinds of malformations. Severity of anemia often needs transfusional support in the first months of life. We describe here a patient with Diamond Blackfan anemia related to a RPL5 mutation. The patient had no physical abnormalities and experienced a very late onset of transfusion dependency.