Activation of Intestinal HIF2α Ameliorates Iron-Refractory Anemia.

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.

Niraparib-induced pure red cell aplasia.

INTRODUCTION: Niraparib, a strong poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor, contributed significantly to progression-free survival as a maintenance therapy in the platinum-sensitive period in both first-line and recurrent ovarian cancer, regardless of the BRCA mutation. Grade 3-4 anemia, which has a manageable side effect profile, especially hematological, is seen in almost 1 out of every 4 patients. To the best of our knowledge, there has been no reported case of pure red cell aplasia (PRCA) induced by niraparib treatment. CASE REPORT: A 65-year-old woman diagnosed with stage 3 serous carcinoma of the tuba received niraparib front-line maintenance treatment had grade 4 anemia after 3 months of niraparib treatment. She underwent bone marrow aspiration and biopsy because of refractory anemia, which needs red blood cell (RBC) transfusions despite interruption of treatment. MANAGEMENT AND OUTCOME: The patient was treated with 1 mg/kg methyl prednisolone, after histopathological assessment was consistent with PRCA. The hemoglobin count returned to the normal range with steroid treatment. DISCUSSION: In daily practice, it should be kept in mind that in the case of refractory anemia induced by niraparib, the underlying cause might be PRCA and can be improved with steroid administration.

Nonsteroidal anti-inflammatory drugs as a targeted therapy for bone marrow failure in Ghosal hematodiaphyseal dysplasia.

Advances in genomic diagnostics hold promise for improved care of rare hematologic diseases. Here, we describe a novel targeted therapeutic approach for Ghosal hematodiaphyseal dysplasia, an autosomal recessive disease characterized by severe normocytic anemia and bone abnormalities due to loss-of-function mutations in thromboxane A synthase 1 (TBXAS1). TBXAS1 metabolizes prostaglandin H2 (PGH2), a cyclooxygenase (COX) product of arachidonic acid, into thromboxane A2. Loss-of-function mutations in TBXAS result in an increase in PGH2 availability for other PG synthases. The current treatment for Ghosal hematodiaphyseal dysplasia syndrome consists of corticosteroids. We hypothesize that nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit COX-1 and COX-2, could ameliorate the effects of TBXAS1 loss and improve hematologic function by reducing prostaglandin formation. We treated 2 patients with Ghosal hematodiaphyseal dysplasia syndrome, an adult and a child, with standard doses of NSAIDs (aspirin or ibuprofen). Both patients had rapid improvements concerning hematologic parameters and inflammatory markers without adverse events. Mass spectrometry analysis demonstrated that urinary PG metabolites were increased along with proinflammatory lipoxygenase (LOX) products 5-hydroxyeicosatetraenoic acid and leukotriene E4. Our data show that NSAIDs at standard doses surprisingly reduced both COX and LOX products, leading to the resolution of cytopenia, and should be considered for first-line treatment for Ghosal hematodiaphyseal dysplasia syndrome.

Salvage Intrapartum Splenectomy for the Treatment of Transfusion-refractory Anaemia in a ß-thalassemia Intermedia Patient.

Thalassemia intermedia (TI) patients may need a transfusion during physiological stress conditions, such as pregnancy. We present a case of a female TI patient with emerging transfusion-refractory anaemia during pregnancy, which resolved after splenectomy performed simultaneously with cesarean delivery. A 26-year pregnant woman at 29th gestational weeks was referred with a diagnosis of TI due to emerging anaemia which was refractory to transfusion. Splenectomy at term was decided to improve anaemia, and transfusion response. A preterm infant was delivered by cesarean section due to threatened preterm labour. Once the uterine incision was closed, an open splenectomy was performed. Postoperative follow-up was uneventful. To the best of our knowledge, the present case is the first open splenectomy performed during cesarean delivery as a salvage option for the management of transfusion-refractory anaemia. Key Words: Thalassemia intermedia, Splenectomy, Pregnancy, Hemolytic anaemia.

Novel TBXAS1 variants in two Indian children with Ghosal hematodiaphyseal dysplasia: A concise report.

Ghosal hematodiaphyseal dysplasia (GHDD) is a rare, autosomal recessive condition characterised by diaphyseal dysplasia of long bones with defective haematopoiesis. We describe 2 such cases with clinical and radiological evidence of GHDD. Molecular analysis revealed novel variants in TBXAS1 gene in both of them. Suspicion and confirmation of this entity is crucial in cases of refractory anemia with bony deformities, as the clinical manifestations in this entity are usually well responsive to corticosteroids.

Clinical Application for Diagnosis of Myelodysplatic/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis.

BACKGROUND: Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/ MPN-RS-T) was newly introduced as a full entity in the 2016 revision of the WHO classification. In this study, we investigated the morphologic, laboratory, and clinical features of MDS/MPN-RS-T. METHODS: We reviewed the bone marrow and genetic studies of patients whose diagnoses were coded as "refractory anemia with ring sideroblasts (RARS)" or "MDS/MPN, unclassifiable" between January 2008 and April 2018. RESULTS: A total of 8 cases fulfilled the criteria for a diagnosis of MDS/MPN-RS-T. All of them had no specific symptoms. Half of the cases had less than 450 × 109/L platelet counts by an automated hematology analyzer; however, all platelet counts exceeded 450 × 109/L when performed manually. JAK2 mutation tests were performed in 7 cases, and a heterozygous mutation was detected in 1 case. SF3B1 mutations were present in 3 of the 4 cases tested. CONCLUSIONS: When RARS is suspected in patients without thrombocytopenia, manual platelet counts should be performed. For patients with suspected essential thrombocythemia, RS evaluation through careful observation of an iron-stained slide is crucial. Since the independent evaluation of RS was reflected in the revised classification, the ambiguous disease classification becomes clearer and more consistent.

Incidence and survival estimates for patients with myelodysplastic syndrome in the early 21st century: no evidence of improvement over time.

We examine changes in population level incidence and survival of patients diagnosed with myelodysplastic syndrome (MDS) in the United States in 2001-2016. Data were extracted from the Surveillance, Epidemiology, and End Results (SEER)-18 database. Period analysis was used to calculate one-, two-, and five-year survival. The incidence peaked at 5.6 per 100,000 in 2010 then decreased to 3.9 by 2016, with a decrease in the diagnoses of refractory anemia (RA) and RA with ringed sideroblasts (RARS) and a relative increase in RA with excess blasts (RAEB). Overall, one-, two-, and five-year relative survival decreased over time, going from 74.3%, 60.9%, and 42.3%, respectively, in 2008-2010 to 70.9%, 55.9%, and 37.6%, respectively, in 2014-2016. When survival was examined by histology, patients with RA/RARS and RAEB had similar survival expectations in 2008-2010 versus 2014-2016 and a decrease was observed for 5q-MDS. Our results highlight the need for new treatment options in MDS.

Successful treatment with tocilizumab for refractory anemia and slowly progressive renal glomerulosclerosis in multicentric Castleman disease: A case report.

RATIONALE: Multicentric Castleman disease (MCD) is a rare lymphoproliferative disorder accompanied by systemic symptoms characterized by polyclonal hypergammaglobulinemia and chronic inflammation due to overexpression of interleukin-6. Histological heterogeneity of renal involvement in MCD has been described, although the number of reports is limited. Tocilizumab, a humanized anti-interleukin-6 receptor antibody, has been reported to be effective for MCD. PATENT CONCERNS: A 64-year-old man experienced refractory anemia and slowly progressive renal dysfunction with proteinuria, accompanied by persistent inflammation for 11 years. DIAGNOSIS: Two renal biopsies were obtained. The first biopsy performed 7 years before admission revealed non-specific interstitial inflammation, whereas the second biopsy demonstrated global sclerosis in most glomeruli and interstitial fibrosis. The patient had multiple lymphadenopathies. Cervical lymph node biopsy histological findings were compatible with plasma cell type Castleman disease. The patient had no evidence of human hepatitis virus-8 infection. INTERVENTION: The patient was treated with 60 mg/d prednisolone followed by 8 mg/kg intravenous tocilizumab every 2 weeks. OUTCOME: His anemia significantly improved, as well as a marked reduction in proteinuria and stabilization of renal function. He did not experience renal function during the 2-years follow-up period. LESSONS: The heterogeneity of the renal manifestations of MCD sometimes makes early diagnosis difficult. We need to interpret the histological findings of the renal biopsy carefully. For advanced-stage renal diseases, tocilizumab might be an effective treatment strategy for MCD.

[Hematologic responses to avatrombopag switch in TPO-RA refractory aplastic anemia].

Objective: Short-term efficacy and safety of afatrombopag conversion therapy in patients with aplastic anemia (AA) who were previously ineffectively treated with intense immunosuppressive therapy (IST) combined with TPO receptor Agonist (TPO-RA) or who were unable to tolerate the side effects of TPO-RA. Methods: Analysis of patients with severe aplastic anemia (SAA) treated in Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College from January 2021 to December 2021 who received IST combined with TPO-RA (eltrombopag/hatrombopag) for at least 6 months, but was ineffective for at least 3 months or patients who cannot continue to use TPO-RA due to side effects, and switched from TPO-RA to avatrombopag (APAG) , and treated for at least 6 months. This study analyzed its short-term efficacy and evaluated its safety. Results: The median age was 54 (14-68) years old among the 16 patients with AA (8 male and eight female) . A total of ten patients (refractory group) who did not respond to IST combined with TPO-RA were converted to APAG median therapy for 6 (6-10) months. Only seven patients (70% ) obtained trilineage HR [four cases of complete treatment response (CTR) , one case of good treatment response (GPR) , and two cases of partial treatment response (PR) ], all of which began to take effect at 3 months of APAG treatment. There were six patients with TPO-RA intolerance, and APAG was treated for 6 (2 to 8) months. About four patients (67% ) received HR (three GPR cases and one PR case) , of which two patients received PR at 3 months and four patients received HR at 6 months of APAG treatment. No APAG-related grade 2 or more adverse events occurred during the APAG therapy, no thrombotic events occurred, no fibrologic tissue hyperplasia was found in the bone marrow pathology reexamination at 6 months of treatment, and none of the patients discontinued the drug due to adverse events. Conclusion: APAG may be a better switching treatment option for patients with AA who are refractory or are intolerant to TPO-RA.

The cell body space occupied by the nucleus during the cell differentiation in human lymphocytic, granulocytic and erythroid cell lineages.

The present nuclear and cell body diameter measurements demonstrated size differences of the approximate cell space estimate occupied by the cell nucleus during the cell differentiation in lymphocytic, granulocytic and erythroid cell lineages. These lineages were used as convenient models because all differentiation steps were easily identified and accessible in diagnostic peripheral blood or bone marrow smears of blood donors (BDs), patients suffering from chronic lymphocytic leukemia (CLL), patients with chronic myeloid leukemia (CML) and refractory anemia (RA) of the myelodysplastic syndrome (MDS). The cell space occupied by the nucleus was constant and did not change during the cell differentiation in the lymphocytic cell lineages of BDs and CLL patients despite the decreased cell size. In contrary, the cell space occupied by the nucleus markedly decreased in differentiating cells of granulocytic and erythroid lineages of patients suffering from CML. In the erythroid cell lineage in patients with RA of MDS the small reduction of the cell space occupied by the nucleus during the differentiation was not significant. The measurements also indicated that in progenitor cells of all studied cell lineages nuclei occupied more than 70 % of the cell space. Thus, the nucleus-cytoplasmic morphological and functional equilibrium appeared to be characteristic for each differentiation step and each specific cell lineage.

Clinical effectiveness of DNA methyltransferase inhibitors and lenalidomide in older patients with refractory anemia with ring sideroblasts: a population-based study in the United States.

Existing studies regarding the role of DNA methyltransferase inhibitors (DNMTi) and lenalidomide in refractory anemia with ring sideroblasts (RARS) are limited. Using the surveillance, epidemiology, and end results-medicare database, we assembled a population-based cohort of older adults diagnosed with non-del(5q) lower-risk myelodysplastic syndromes during 2007-2015. Of 2167 patients, 30% had RARS. About 16% of RARS and non- ring sideroblasts (RS) patients received DNMTi. RARS patients were more likely to receive lenalidomide (11.1% vs. 7.1%, p < 0.01). Among patients who were transfusion-dependent at treatment initiation, 55.6% of those treated with DNMTi only and 42.5% treated with lenalidomide only achieved red blood cell transfusion independence (RBC-TI) for a median duration of 21 and 12 weeks, respectively. RS status did not impact rate of RBC-TI. RARS patients had a significantly better survival, and the median survival of RARS patients varied by treatment group. In this population-based study of older RARS patients, DNMTi and lenalidomide were clinically active.

Associação incomum entre fenótipo e genótipo em dois pacientes com câncer hematológico / Unusual association between phenotype and genotype in two patients with hematological cancer

Descrição: Relato de caso de um paciente com um transcrito raro (e1a2) na Leucemia Mieloide Crônica (LMC) e outro com uma translocação rara na Síndrome Mielodisplásica (SMD). Discussão: O transcrito e1a2 possui frequência de 1% entre os casos de LMC, já a translocação t(11,17)(q23;q21) não foi evidenciada em paciente com SMD do tipo Anemia Refratária com Excesso de Blastos (AREB) do tipo 2. Conclusão: Ambos os casos apresentados possuem associação incomum entre fenótipo e genótipo. A correlação da clínica com os achados laboratoriais é importante para a determinação fidedigna do diagnóstico e prognóstico destes pacientes.

Description: Case report of a patient with a rare transcript (e1a2) in Chronic Myeloid Leukemia (CML) and another with a rare translocation in Myelodysplastic Syndrome (SMD). Discussion: The transcript e1a2 has a frequency of 1% in CML cases, whereas t (11,17) (q23; q21) translocation was not observed in a patient with type of Refractory Anemia with Excess Blasts (AREB) type 2. Conclusion: Both cases reported have unusual association between phenotype and genotype. The correlation of the clinic with the laboratory findings is important for the reliable determination of the diagnosis and prognosis of these patients.

Novel compound heterozygous variants of TBXAS1 presenting with Ghosal hematodiaphyseal dysplasia treated with steroids.

BACKGROUND: Homozygous or compound heterozygous pathogenic variants in the thromboxane A synthase 1 (TBXAS1) gene are associated with Ghosal hematodiaphyseal dysplasia (GHDD) which is characterized by defective hematopoiesis and increased bone density of long bones. METHODS: Patients 1 and 2 are identical twins, who presented with red blood cell transfusion-dependent normocytic anemia and thrombocytopenia with bone marrow fibrosis and cortical bone thickening of long bones on plain radiograph. To clarify the etiology of their anemia and thrombocytopenia, whole blood was used for the DNA extraction and analyzed using next-generation sequencing (NGS) on an in-house bone marrow failure syndrome panel. RESULTS: The NGS results indicated that these two patients carried two heterozygous variants in TBXAS1, exon7, c.583_584del, p.Ala195Leufs*12, and exon12, c.1420G>T, p.Gly474Trp, which were inherited from their mother and father, respectively. Patients 1 and 2 have been on chronic oral steroids with normalization of hemoglobin and platelet count after steroid initiation. Patient 3 is their sister who has normal blood counts but also has the same variants in TBXAS1 as her brothers. Radiographs showed cortical bone thickening and she has not required any treatment or transfusion. CONCLUSION: We report three Caucasian siblings from non-consanguineous parents with novel compound heterozygous variants of TBXAS1 presenting with the phenotypes of GHDD. These three cases illustrate the variable clinical expressivity of the GHDD from two-compound heterozygous pathogenic variants of TBXAS1.

[Treatment-refractory anaemia in a 35-year-old heart transplant recipient on chronic hemodialysis]. / Therapierefraktäre Anämie bei einem 35-jährigen Dialysepatienten nach Herztransplantation.

This article presents a case of pure red cell aplasia in a 35-year-old heart transplant recipient on chronic hemodialysis. Elevated parvovirus B19 immunoglobulin M blood levels were detected along with a high viral load of 80 billion IU/ml quantified by polymerase chain reaction. Bone marrow examination revealed giant proerythroblasts confirming parvovirus B19 infection. High-dose intravenous immunoglobulin was used for treatment. Anaemia had significantly improved 4 weeks later. Parvovirus B19 infection should be excluded in organ transplant recipients with anaemia due to ineffective erythropoiesis.