A Case of Refractory Anemia in Patient of Chronic Kidney Disease and the Challenges in its Management.

Anemia is a common complication of chronic kidney disease (CKD) that has been classically attributed to inadequate production of endogenous erythropoietin.1 Though there are many other common causes of refractory anemia in CKD like iron deficiency, vitamin B12, and folic acid deficiency, noncompliance to dialysis and erythropoietin therapy rare causes like blood loss, bone marrow failure, infections causing aplastic crisis like CMV, parvovirus B19 should be ruled out. Parvovirus has an extreme tropism for erythroid cells and is an uncommon cause of anemia in patients with CKD on maintenance dialysis (MHD) and on erythropoietin.2 Here we are reporting a rare case of refractory anemia in a patient of CKD on MHD secondary to parvovirus-related aplastic crisis. How to cite this article: Gade K, Londhe C, Pednekar S, et al. A Case of Refractory Anemia in Patient of Chronic Kidney Disease and the Challenges in its Management. J Assoc Physicians India 2023;71(10):94-95.

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.

Refractory anemia with ring sideroblasts (RARS) and RARS with thrombocytosis: "2019 Update on Diagnosis, Risk-stratification, and Management".

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.

Study for the diagnostic screening of paroxsymal nocturnal hemoglobinuria in Turkey: Prospective multicentric evaluation of suspected patients.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease presenting with variable and various clinical findings. PNH might be overlooked and diagnosis may be delayed due to low awareness about PNH. This is the first multicenter study in Turkey, investigating the efficiency of diagnostic screening of PNH by multiparameter flow cytometry (FCM) according to consensus guidelines. METHODS: We evaluate the efficiency of consensus clinical indications for PNH testing with FCM in 1689peripheral blood samples from 20 centers between January 2014 and December 2017. RESULTS: Overall, at the 20 centers contributing to this study, PNH clone were detected in 62/1689 samples (3.6%) by FCM test. 75.8% (n = 47) of patients with PNH clone had aplastic anemia, 3.2% (n = 2) had Coombs (-) hemolytic anemia, 6.5% (n = 4) had unexplained cytopenia, 3.2% (n = 2) had MDS with refractory anemia, 1.6% (n = 1) had hemoglobinuria and 9.7% (n = 6) had others (elevated LDH, splenomegaly, etc.). In contrast, we detect no PNH clone test in patients who were screened for unexplained thrombosis. CONCLUSIONS: Our study showed that current clinical indications for PNH testing are highly efficient and diagnostic screening of suspected patients for PNH with FCM is recommended. However, advanced screening algorithms are required for patients presenting with unexplained thrombosis and normal complete blood count.

Refractory anemia with ring sideroblasts (RARS) and RARS with thrombocytosis (RARS-T): 2017 update on diagnosis, risk-stratification, and management.

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 (similar to BCR-ABL1 negative MPN). 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; with ASXL1/SETBP1 mutations adversely impacting survival. Cytogenetic abnormalities are uncommon in both diseases. RISK STRATIFICATION: Most patients with MDS-RS-SLD are stratified into lower risk groups by the revised-International Prognostic Scoring System (R-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 TREATMENT: Anemia and iron overload are complications seen in both and are managed similar to lower risk MDS and MPN. Aspirin therapy is reasonable in MDS/MPN-RS-T, especially in the presence of JAK2V617F, but the value of platelet-lowering drugs is uncertain.

Steroid-responsive anemia in patients of Ghosal hematodiaphyseal dysplasia: simple to diagnose and easy to treat.

Ghosal hematodiaphyseal dysplasia (GHDD) is a recently recognized cause of steroid-responsive anemia. We would like to report 3 cases of GHDD who presented in early childhood with moderate to severe anemia, splenomegaly, and a hypocellular marrow with increased reticulin. They were easily diagnosed with long-bone x-rays showing diaphyseal and metaphyseal widening and loss of diaphyseal constriction. All cases dramatically responded to oral steroid and no longer needed blood transfusion. They required steroid at low doses for long term (up to 5 y). GHDD is easy to diagnose with long-bone radiography and consistently responds to steroid. It should therefore be considered as a differential diagnosis of unusual anemia in early childhood, especially in children from the Middle East or the Indian subcontinent.

Hyperuricemia and acute kidney injury secondary to spontaneous tumor lysis syndrome in low risk myelodysplastic syndrome.

BACKGROUND: This is a rare instance of acute kidney injury caused by hyperuricemia due to spontaneous tumor lysis syndrome and also the first case of spontaneous tumor lysis syndrome reported in association with myelodysplastic syndrome. CASE PRESENTATION: A 53-year-old man presented with abrupt oliguria. Laboratory findings on admission included hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis and rapidly rising serum creatinine, which were consistent with acute tumor lysis syndrome in the absence of precipitating chemotherapy or radiotherapy. After hemodialysis and oral uric acid lowering therapy, serum uric acid levels returned to normal range and renal function rapidly recovered. The patient was diagnosed as myelodysplastic syndrome eleven months later. CONCLUSIONS: Occult malignancy including solid tumors and hematological malignancies should be carefully evaluated in the case of unexplainable acute kidney injury with hyperuricemia. Aggressive investigations should be thoroughly considered and repeated in this population.

Molecular similarity between myelodysplastic form of chronic myelomonocytic leukemia and refractory anemia with ring sideroblasts.

Chronic myelomonocytic leukemia is similar to but a separate entity from both myeloproliferative neoplasms and myelodysplastic syndromes, and shows either myeloproliferative or myelodysplastic features. We ask whether this distinction may have a molecular basis. We established the gene expression profiles of 39 samples of chronic myelomonocytic leukemia (including 12 CD34-positive) and 32 CD34-positive samples of myelodysplastic syndromes by using Affymetrix microarrays, and studied the status of 18 genes by Sanger sequencing and array-comparative genomic hybridization in 53 samples. Analysis of 12 mRNAS from chronic myelomonocytic leukemia established a gene expression signature of 122 probe sets differentially expressed between proliferative and dysplastic cases of chronic myelomonocytic leukemia. As compared to proliferative cases, dysplastic cases over-expressed genes involved in red blood cell biology. When applied to 32 myelodysplastic syndromes, this gene expression signature was able to discriminate refractory anemias with ring sideroblasts from refractory anemias with excess of blasts. By comparing mRNAS from these two forms of myelodysplastic syndromes we derived a second gene expression signature. This signature separated the myelodysplastic and myeloproliferative forms of chronic myelomonocytic leukemias. These results were validated using two independent gene expression data sets. We found that myelodysplastic chronic myelomonocytic leukemias are characterized by mutations in transcription/epigenetic regulators (ASXL1, RUNX1, TET2) and splicing genes (SRSF2) and the absence of mutations in signaling genes. Myelodysplastic chronic myelomonocytic leukemias and refractory anemias with ring sideroblasts share a common expression program suggesting they are part of a continuum, which is not totally explained by their similar but not, however, identical mutation spectrum.

Refractory anaemia in an immunocompromised patient--what is it?

Anaemia is common among human immunodeficiency virus (HIV)-infected patients. It may be directly attributable to the virus or may be caused by opportunistic infections, neoplasms or drugs that cause either bone marrow suppression or haemolysis. Pure red cell aplasia (PRCA) is an uncommon haematological disorder that causes severe transfusion dependant anaemia. We report a 36 year-old female with HIV infection who developed anaemia which did not improve even after discontinuing the offending drug, namely Zidovudine. Routine investigations were unhelpful but her bone marrow study was consistent with pure red cell aplasia. She showed dramatic improvement with steroids with subsequent transfusion independence.

[Refractory anemias]. / Les anemies réfractaires.

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.

Morphological differentiation of severe aplastic anaemia from hypocellular refractory cytopenia of childhood: reproducibility of histopathological diagnostic criteria.

AIMS: To evaluate the reproducibility and reliability of the histomorphological criteria differentiating severe aplastic anaemia (SAA) and hypoplastic refractory cytopenia of childhood (RCC), the most frequently acquired hypocellular bone marrow conditions of childhood. METHODS AND RESULTS: We performed a double-blind interobserver study of 100 different cases of SAA and RCC among seven haematopathologists of the European Working Group of MDS in Childhood (EWOG-MDS) and the German SAA study. Cases with foci of typical myelodysplastic syndrome (MDS) morphology, such as patchy erythropoiesis with defective maturation, in an otherwise highly hypocellular or adipocytic bone marrow were classified as having RCC. Bone marrow samples without a patchy distribution, few scattered myeloid cells or haematopoietic aplasia were diagnosed as SAA. In only four of 100 cases did the reference pathologists not reach agreement regarding classification as SAA or RCC. The kappa index was 0.79. CONCLUSIONS: Our results show that the vast majority of SAA and RCC cases can be reliably differentiated by morphological means alone. A clear differentiation between SAA and RCC at presentation is mandatory for optimizing therapy strategies, and might be responsible for the fact that, in the German childhood SAA study, the probability of developing clonal disease after immunosuppressive therapy has dropped to 3%.

A new diagnosis of myelodysplastic syndrome in hemochromatosis in an elderly man.

Hemochromatosis is associated with increased risk of hematological neoplasias, but studies showing hemochromatosis gene mutations in myelodysplastic syndrome (MDS) are scanty, particularly in the elderly. The onset of MDS in hemochromatosis usually occurs between 60 and 70 years of age, while cases with advanced age are very rare. We report a case of a 78- year-old man with hemochromatosis who developed refractory anemia with excess of blasts. Our case suggests that in the elderly with hemochromatosis, myelodysplasia should be considered a possible cause of anemia.

Cytogenetic profile of Indian patients with de novo myelodysplastic syndromes.

BACKGROUND & OBJECTIVES: Myelodysplastic syndrome (MDS) is a clonal haematopoietic stem cell disorder characterized by ineffective haematopoiesis and leukaemia progression. Cytogenetic analysis has proven to be a mandatory part of the diagnosis of MDS as well as a major indicator for predicting clinical course and outcome. Studies on cytogenetics of MDS are reported mostly from the West and only a few are available from Asian countries. We report herein cytogenetic studies on 40 Indian patients with primary MDS to find out the occurrence and type of chromosome abnormalities and recurring defects. METHODS: Cytogenetic analysis was done using GTG banding and karyotyped according to the International System for Human Cytogenetic Nomenclature (ISCN). RESULTS: Of the 40 patients, 19 patients (47.5%) showed clonal karyotypic abnormalities with distribution as follows: 3 of 15 (20%) of refractory anaemia (RA), 4 of 7 (57%) of refractory anaemia with excess blasts-1 (RAEB-1), 4 of 6 (67%) of refractory anaemia with excess blasts 2 (RAEB-2), 2 of 3 (67%) of refractory anaemia with ring sideroblasts (RARS), 2 of 4 (50%) of refractory cytopenia with multilineage dysplasia (RCMD), none (0%) RCMD-ringed sideroblasts (RCMD-RS) and 4 patients with 5q syndrome. The frequent abnormalities observed in our study were -7, 5q-and trisomy 8. INTERPRETATION & CONCLUSIONS: Two rare chromosomal abnormalities (6q-, 3q-) were found with unknown prognostic significance. Hence, cytogenetic analysis may be incorporated in the routine diagnosis of MDS since there are racial differences in clinical pictures and the molecular events.

Is refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T) a necessary or useful diagnostic category?

Both the 2001 World Health Organisation (WHO) classification of haematopoietic neoplasms and the 2008 WHO classification revision include a distinctive diagnostic category, refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T), to describe those rare patients who have both >or=15% ring sideroblasts and a sustained elevated platelet count. Recently, it has become clear that patients meeting WHO criteria for RARS-T have clonal JAK2(V617F) and MPL(W515) mutations at a similar rate to essential thrombocythaemia (ET). Given that the provisional classification of RARS-T as a myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndrome, rather than as a form of MPN (i.e., ET), rests principally upon the presence of ring sideroblasts, which are a non-specific morphological finding, these new molecular results prompt reconsideration of the necessity for a distinctive RARS-T category. Here we review the historical developments that led up the definition of RARS-T as a disease entity, and we discuss conceptual understanding of RARS-T and arguments against continued use of RARS-T as a separate diagnostic category.