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British Journal of Haematology Jan 2021A previous dose-finding study has suggested that romiplostim is effective in patients with refractory aplastic anaemia (AA) and 10 µg/kg once weekly was recommended as...
A previous dose-finding study has suggested that romiplostim is effective in patients with refractory aplastic anaemia (AA) and 10 µg/kg once weekly was recommended as a starting dose. In this Phase II/III, multicentre, open-label study, romiplostim was administered subcutaneously at a fixed dose of 10 µg/kg once weekly for 4 weeks (weeks 1-4) followed by weekly doses (5, 10, 15 and 20 µg/kg) titrated by platelet response for up to 52 weeks (weeks 5-52). A total of 31 patients with AA who were refractory to immunosuppressive therapy (IST) and thrombocytopenia (platelet count of ≤30 × 10 /l) were enrolled. The primary efficacy endpoint of the proportion of patients achieving any haematological (platelet, neutrophil and erythrocyte) response at week 27 was 84% [95% confidence interval (CI) 66-95%]. Trilineage response was 39% (95% CI 22-58%) at week 53. The most common treatment-related adverse events (AEs) were headache and muscle spasms (each 13%). All AEs were mild or moderate except for three patients with Grade 3 hepatic AEs; no AEs necessitated romiplostim discontinuation. Two patients developed cytogenetic abnormalities, of whom one returned to normal karyotype at last follow-up. High-dose romiplostim is effective and well tolerated in the treatment of patients with AA refractory to IST.
Topics: Adult; Aged; Anemia, Aplastic; Anemia, Refractory; Blood Cell Count; Female; Headache; Hematopoiesis; Humans; Male; Middle Aged; Receptors, Fc; Recombinant Fusion Proteins; Spasm; Thrombopoietin; Treatment Outcome; Young Adult
PubMed: 33152120
DOI: 10.1111/bjh.17190 -
Mediterranean Journal of Hematology and... 2021Anemia is a global health problem affecting one-third of the world population, and half of the cases are due to iron deficiency (ID). Iron deficiency anemia (IDA) is the... (Review)
Review
Anemia is a global health problem affecting one-third of the world population, and half of the cases are due to iron deficiency (ID). Iron deficiency anemia (IDA) is the leading cause of disability in several countries. Although multiple mechanisms may coexist, ID and IDA causes can be classified as i) insufficient iron intake for the body requirement, ii) reduced absorption, and iii) blood losses. Oral iron represents the mainstay of IDA treatment. IDA is defined as "refractory" when the hematologic response after 4 to 6 weeks of treatment with oral iron (an increase of >=1 g/dL of Hb) is absent. The cause of iron-refractory anemia is usually acquired and frequently related to gastrointestinal pathologies, although a rare genetic form called iron-refractory iron deficiency anemia (IRIDA) exists. In some pathological circumstances, either genetic or acquired, hepcidin increases, limiting the absorption in the gut, remobilization, and recycling of iron, thereby reducing iron plasma levels. Indeed, conditions with high hepcidin levels are often under-recognized as iron refractory, leading to inappropriate and unsuccessful treatments. This review provides an overview of the iron refractory anemia underlying conditions, from gastrointestinal pathologies to hepcidin dysregulation and iatrogenic or provoked conditions, and the specific diagnostic and treatment approach.
PubMed: 34007416
DOI: 10.4084/MJHID.2021.028 -
Clinical Lymphoma, Myeloma & Leukemia Jan 2019Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are hybrid group of chronic myeloid neoplasms combining features of both MDS and MPN. The World Health... (Review)
Review
Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are hybrid group of chronic myeloid neoplasms combining features of both MDS and MPN. The World Health Organization classification coined this group designation in 2008 to include chronic myelomonocytic leukemia, atypical chronic myeloid leukemia, juvenile myelomoncoytic leukemia, refractory anemia with ring sideroblasts and thrombocytosis as a provisional entity, and MDS/MPN unclassified. In this review, we highlight the challenges in diagnosing this group of the diseases, summarize the updates in classification, and discuss recent evolving understanding of the genetic landscape. We review risk-stratification models and overview the current management largely adapted from current MDS or MPN therapies. We define clinical benefit of therapy based on new proposed response criteria developed specifically for these groups of neoplasms. Finally, we introduce future opportunities including the planned international ABN MARRO (A Novel therapy combinations in untreated MDS/MPN And Relapsed/Refractory Overlap Syndromes) clinical study led by the MDS/MPN International Working Group.
Topics: Humans; Myelodysplastic-Myeloproliferative Diseases
PubMed: 30555034
DOI: 10.1016/j.clml.2018.11.019 -
American Journal of Hematology Jun 2015Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include... (Review)
Review
DISEASE OVERVIEW
Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include refractory anemia with ring sideroblasts (RARS) and RARS with thrombocytosis (RARS-T).
DIAGNOSIS
RARS is a lower risk myelodysplastic syndrome (MDS) with dysplasia limited to the erythroid lineage, <5% bone marrow (BM) blasts and ≥15% BM RS. RARS-T is a provisional entity in the MDS/MPN (myeloproliferative neoplasm) overlap syndromes, with diagnostic features of RARS, along with a platelet count ≥450 × 10(9)/L and large atypical megakaryocytes similar to those observed in BCR-ABL1 negative MPN. Mutations and Karyotype: Mutations in the SF3B1 gene are seen in ≥80% of patients with RARS and RARS-T, and strongly correlate with the presence of BM RS; RARS-T patients have additional mutations such as, JAK2V617F (∼60%), MPL (<5%), and CALR (<5%). Cytogenetic abnormalities are uncommon in both RARS and RARS-T.
RISK STRATIFICATION
Most patients with RARS are stratified into lower risk groups by the International Prognostic Scoring System (IPSS) for MDS and the revised IPSS. Disease outcome in RARS-T is better than that of RARS, but worse than that of essential thrombocytosis. Both RARS and RARS-T have a low risk of leukemic transformation.
TREATMENT
Anemia and iron overload are complications in both diseases and are managed similar to lower risk MDS. Aspirin therapy is reasonable in RARS-T, especially in the presence of JAK2V617F, but the value of platelet-lowering drugs is uncertain. Case reports of RARS-T therapy with lenalidomide warrant additional studies.
Topics: Anemia, Refractory; Anemia, Sideroblastic; Angiogenesis Inhibitors; Aspirin; Female; Humans; Iron Overload; Janus Kinase 2; Lenalidomide; Male; Mutation; Myelodysplastic Syndromes; Phosphoproteins; Platelet Aggregation Inhibitors; RNA Splicing Factors; Receptors, Thrombopoietin; Ribonucleoprotein, U2 Small Nuclear; Risk Factors; Thalidomide; Thrombocytosis
PubMed: 25899435
DOI: 10.1002/ajh.24038 -
Revista Espanola de Enfermedades... Jul 2011refractory iron-deficiency anemia has a multifactorial origin related to various gastrointestinal conditions, with celiac disease plus malabsorption and IBD together...
INTRODUCTION
refractory iron-deficiency anemia has a multifactorial origin related to various gastrointestinal conditions, with celiac disease plus malabsorption and IBD together with isolated gluten intolerance being most common.
OBJECTIVES
to determine the prevalence of serum, genetic, and histological markers for gluten intolerance, and to analyze the response to gluten withdrawal from the diet in these patients.
METHODS
a number of patients with refractory anemia were prospectively and consecutively enrolled. A protocol to measure serum (TGt-2), genetic (HLA-DQ2/DQ8), and histological markers for celiac disease was applied. All followed a gluten-free diet for a median 3.6 years. Sustained remission of anemia during follow-up was interpreted as positive response.
RESULTS
ninety-eight patients (84% females) with a mean age of 54 years were studied. Anti-TGt2 antibodies were positive in 5% of cases. A total of 67 cases (68%) were haplotype HLA-DQ2 or -DQ8 (+). We found villous atrophy (Marsh III) in 13% of patients, and an inflammatory pattern (Marsh I or II) in 13%. All remaining 72 patients (74%) had no histological duodenal changes.Age, anemia duration, number of transfusions, number of parenteral iron doses, and time on a gluten-free diet were all compared according to the presence or absence of villous atrophy and HLA-DQ2/8 positivity, and no significant differences were found for any of the analyzed variables. Response was positive in 92% of subjects.
CONCLUSIONS
celiac disease with villous atrophy is rarely a cause of refractory anemia. Gluten intolerance with no histological lesions is seen in almost 75% of patients, and therefore plays a relevant role in its development.
Topics: Adult; Aged; Aged, 80 and over; Anemia, Hypochromic; Atrophy; Biopsy; Blood Chemical Analysis; Celiac Disease; Colonoscopy; Diet, Gluten-Free; Female; Genes, MHC Class II; Genetic Predisposition to Disease; Humans; Immunoglobulins; Liver Function Tests; Male; Middle Aged; Prospective Studies; Young Adult
PubMed: 21770680
DOI: 10.4321/s1130-01082011000700003 -
Revue Medicale de Bruxelles Sep 2013Refractory anemia, also known as myelodysplastic syndromes, forms a group of clonal diseases characterized by cytopenias with mostly rich bone marrow. Preferentially... (Review)
Review
Refractory anemia, also known as myelodysplastic syndromes, forms a group of clonal diseases characterized by cytopenias with mostly rich bone marrow. Preferentially reaching an older population, the prognosis depends on both comorbidities and characteristics of the disease, which have been grouped into a score established in 1997 ("IPSS = International Prognostic Scoring System") and revised in 2012 ("R-IPSS = Revised IPSS"). Overall survival and risk of transformation into acute nonlymphoblastic leukemia can now be estimated fairly accurately. Based on these characteristics, the treatment will be mainly supportive or will use several new molecules: growth factors, lenalidomide, 5-azacitidine, etc. A minority of patients may also benefit from allogeneic BMT or sometimes immunosuppressive therapy.
Topics: Aged; Aged, 80 and over; Anemia, Refractory; Bone Marrow Transplantation; Humans; Immunosuppressive Agents; Prognosis; Risk Assessment
PubMed: 24195247
DOI: No ID Found -
American Journal of Hematology Apr 2019Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include... (Review)
Review
DISEASE OVERVIEW
Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include refractory anemia with ring sideroblasts (RARS), now classified under myelodysplastic syndromes with RS (MDS-RS) and RARS with thrombocytosis (RARS-T); now called myelodysplastic/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T).
DIAGNOSIS
MDS-RS is a lower-risk MDS, with single or multilineage dysplasia (SLD/MLD), <5% bone marrow (BM) blasts and ≥ 15% BM RS (≥5% in the presence of SF3B1 mutations). MDS/MPN-RS-T, now a formal entity in the MDS/MPN overlap syndromes, has diagnostic features of MDS-RS-SLD, along with a platelet count ≥450 × 10(9)/L and large atypical megakaryocytes.
MUTATIONS AND KARYOTYPE
Mutations in SF3B1 are seen in ≥80% of patients with MDS-RS-SLD and MDS/MPN-RS-T, and strongly correlate with the presence of BM RS; MDS/MPN-RS-T patients also demonstrate JAK2V617F, ASXL1, DNMT3A, SETBP1, and TET2 mutations. Cytogenetic abnormalities are uncommon in both.
RISK STRATIFICATION
Most patients with MDS-RS-SLD are stratified into lower-risk groups by the revised-IPSS. Disease outcome in MDS/MPN-RS-T is better than that of MDS-RS-SLD, but worse than that of essential thrombocythemia. Both diseases have a low risk of leukemic transformation.
TREATMENT
Anemia and iron overload are complications seen in both and are managed similar to lower-risk MDS and MPN. The advent of luspatercept, a first-in-class erythroid maturation agent will tremendously boost the ability to manage anemia. Aspirin therapy is reasonable in MDS/MPN-RS-T, especially in the presence of JAK2V617F, but the value of platelet-lowering drugs remains uncertain.
Topics: Anemia, Refractory; Anemia, Sideroblastic; Erythroblasts; Female; Humans; Iron Overload; Male; Mutation; Myelodysplastic-Myeloproliferative Diseases; Thrombocytosis
PubMed: 30618061
DOI: 10.1002/ajh.25397 -
Advanced Science (Weinheim,... Mar 2024In clinics, hepcidin levels are elevated in various anemia-related conditions, particularly in iron-refractory anemia and in high inflammatory states that suppress iron...
In clinics, hepcidin levels are elevated in various anemia-related conditions, particularly in iron-refractory anemia and in high inflammatory states that suppress iron absorption, which remains an urgent unmet medical need. To identify effective treatment options for various types of iron-refractory anemia, the potential effect of hypoxia and pharmacologically-mimetic drug FG-4592 (Roxadustat) are evaluated, a hypoxia-inducible factor (HIF)-prolyl hydroxylase (PHD) inhibitor, on mouse models of iron-refractory iron-deficiency anemia (IRIDA), anemia of inflammation and 5-fluorouracil-induced chemotherapy-related anemia. The potent protective effects of both hypoxia and FG-4592 on IRIDA as well as other 2 tested mouse cohorts are found. Mechanistically, it is demonstrated that hypoxia or FG-4592 could stabilize duodenal Hif2α, leading to the activation of Fpn transcription regardless of hepcidin levels, which in turn results in increased intestinal iron absorption and the amelioration of hepcidin-activated anemias. Moreover, duodenal Hif2α overexpression fully rescues phenotypes of Tmprss6 knockout mice, and Hif2α knockout in the gut significantly delays the recovery from 5-fluorouracil-induced anemia, which can not be rescued by FG-4592 treatment. Taken together, the findings of this study provide compelling evidence that targeting intestinal hypoxia-related pathways can serve as a potential therapeutic strategy for treating a broad spectrum of anemia, especially iron refractory anemia.
Topics: Animals; Mice; Anemia; Anemia, Refractory; Fluorouracil; Glycine; Hepcidins; Hypoxia; Iron; Isoquinolines
PubMed: 38243847
DOI: 10.1002/advs.202307022