DOCSLIB.ORG

Immunome" in the Stratification of Myelodysplastic Syndromes and Future Clinical Trial Design: Systems Immunology; a Way Forward in MDS

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Immunome King’s Research Portal DOI: 10.1200/JCO.19.01823 Document Version Peer reviewed version Link to publication record in King's Research Portal Citation for published version (APA): Winter, S., Shoaie, S., Kordasti, S., & Platzbecker, U. (2020). Integrating the "Immunome" in the Stratification of Myelodysplastic Syndromes and Future Clinical Trial Design: Systems immunology; a way forward in MDS. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 38(15), 1723-1735. [jco.19.01823]. https://doi.org/10.1200/JCO.19.01823 Citing this paper Please note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this may differ from the final Published version. If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections. General rights Copyright and moral rights for the publications made accessible in the Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognize and abide by the legal requirements associated with these rights. •Users may download and print one copy of any publication from the Research Portal for the purpose of private study or research. •You may not further distribute the material or use it for any profit-making activity or commercial gain •You may freely distribute the URL identifying the publication in the Research Portal Take down policy If you believe that this document breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 26. Sep. 2021 1 Journal of Clinical Oncology 2 Review Article 3 Integrating the ‘Immunome’ in the stratification of myelodysplastic syndromes 4 and future clinical trial design 5 Running title: Systems immunology; a way forward in MDS 6 Authors: Susann Winter1,3, Saeed Shoaie2, Shahram Kordasti‡3,4, Uwe Platzbecker5,6,7,3,4 7 Date of acceptance: 7th January 2020 8 Affiliations: 9 1 Department of Internal Medicine I, University Hospital Carl Gustav Carus, Technical 10 University Dresden, Germany; German Cancer Consortium (DKTK), partner site Dresden; and 11 German Cancer Research Center (DKFZ), Heidelberg, Germany 12 2 Centre for Host-Microbiome Interactions, Dental Institute, King’s College London, UK 13 3 Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, King’s College 14 London, UK 15 4 Haematology Department, Guy’s Hospital, London, UK 16 5 Medical Clinic and Policlinic 1, Haematology and Cellular Therapy, University of Leipzig 17 Medical Center, Germany 18 6 German MDS Study Group (G-MDS), Leipzig, Germany 19 7 German Cancer Consortium (DKTK); and German Cancer Research Center (DKFZ), Heidelberg, 20 Germany 21 ‡Correspondence to S.K., e-mail: [email protected], telephone: +44 (0) 20 7848 22 8028, address: Guy’s Hospital, St Thomas Street, London, SE1 9RT 1 23 Abstract 24 Myelodysplastic syndromes (MDS) are characterised by ineffective haematopoiesis and often 25 include a dysregulation and dysfunction of the immune system. In the context of population 26 ageing, MDS incidence is set to rise substantially, with exponential increases in health care 27 costs, given the limited and expensive treatment options for these patients. Treatment 28 selection is mainly based on calculated risk categories according to a Revised International 29 Prognostic Scoring System (IPSS-R). However, although IPSS-R is an excellent predictor of 30 disease progression, it is an ineffective predictor of response to disease-modifying therapies. 31 Redressing these unmet needs, the ‘immunome’ is a key, multifaceted component in the 32 initiation and overall response against malignant cells in MDS, and the current omission of 33 immune status monitoring may in part explain the insufficiencies of current prognostic 34 stratification methods. Nevertheless, integrating these and other recent molecular advances 35 into clinical practice proves difficult. This review highlights the complexity of immune 36 dysregulation in MDS pathophysiology, and the fine balance between smouldering 37 inflammation, adaptive immunity, and somatic mutations in promoting or suppressing 38 malignant clones. We review the existing knowledge and discuss how state-of-the-art immune 39 monitoring strategies could potentially permit novel patient sub-stratification, thereby 40 empowering practical predictions of response to treatment in MDS. We propose novel 41 multicentre studies, which are needed to achieve this goal. 42 Keywords: MDS, immune dysregulation, immune profile, patient stratification 2 43 Introduction 44 Myelodysplastic syndromes (MDS) represent a group of acquired clonal disorders of 45 haematopoietic stem and progenitor cells (HSPCs), characterised by ineffective 46 haematopoiesis, peripheral cytopenias, genetic instability, and an increased risk of 47 progression to acute myeloid leukaemia (AML)1. Considering the higher prevalence in elderly 48 patients, the population ageing in developed countries as well as higher diagnostic awareness, 49 the incidence of MDS is set to rise substantially in coming decades2. 50 Clinical outcomes can vary greatly, even between patients considered to have the same MDS 51 subtype. Thus, MDS display marked heterogeneity regarding prognosis and the risk of disease 52 progression. To overcome this heterogeneity, the IPSS was introduced and then later revised 53 (IPSS-R) with the aim to provide discriminatory prognostic risk assessment regarding overall 54 survival and risk of progression to AML3. Whilst the IPSS-R reliably predicts the risk of disease 55 progression, it is not an effective tool to predict response to disease-modifying therapies4. 56 This is not surprising since the IPSS-R, like the original IPSS, was developed based on clinical 57 data from untreated MDS patients. Recent advances in targeted and large-scale next 58 generation sequencing (NGS) have helped to illuminate the dynamic genomic landscape in 59 MDS5–7. Although none of the most common recurrent somatic mutations is disease-defining, 60 some have an independent impact on overall survival, such as in TP538. Thus, addition of 61 molecular data to the IPSS-R can improve its predictive power5, 8, 9. 62 Recent advances have also highlighted the role of immune dysregulation in MDS pathogenesis 63 but are currently omitted from IPSS-R. This includes both abnormal activation of innate 64 immune pathways and associated inflammation as well as aberrant cellular immune 65 responses of independent prognostic value, which dynamically evolve during disease 3 66 progression10–13. The addition of comprehensive immunologic data to prognostic models 67 could, similar to mutational data, further help to refine risk stratification across the boundary 68 of lower- and higher-risk MDS. We envisage that continued clarification of the immune 69 pathways that are dysregulated in selected MDS subtypes will improve patient stratification, 70 the use and outcomes of existing treatments and novel immunotherapies, and drive the 71 development of new targeted drugs. In this review, we highlight recent advances in the 72 understanding of immune dysregulation in MDS, discuss their clinical implications as well as 73 potential therapeutic applications, and outline how immune profiling could be implemented 74 in future clinical trials. 75 Predisposing and potential driving immune factors 76 a) Smouldering inflammation and immunosenescence 77 Chronic inflammation due to long-lasting exposure to persistent infection or sterile 78 inflammation is a well-established predisposing factor for cancer14, 15, and increasing evidence 79 implicates the activation of innate immune signalling in age-related haematopoietic 80 senescence16, bone loss17, and MDS18. In fact, normal human ageing represents a state of 81 chronic low-grade sterile inflammation, similar to that originally described as ‘para- 82 inflammation’ by Medzhitov19, and commonly referred to as ‘inflammaging’20. Stressed, 83 damaged or otherwise malfunctioning, and/or dead cells release endogenous inducers of 84 sterile inflammation, including damage-associated molecular patterns (DAMPs) like high- 85 mobility-group-protein B1 (HMGB1) and alarmin S100 proteins, which can be sensed through 86 different receptors, such as Toll-like receptors (TLRs) and cytosolic nucleotide-binding domain 87 and leucine-rich repeat pattern recognition receptors (NLRs)19, 20. The physiological purpose 88 of the ensuing inflammatory response early in life and adulthood is to restore functionality 4 89 and homeostasis in the tissue. However, in old age, a period in life largely not foreseen by 90 evolution, the continuous exposure to inflammatory stimuli/stressors (the ‘immune 91 biography’) becomes detrimental, setting the biologic background favouring the susceptibility 92 to age-related inflammatory disorders, autoimmunity, and deterioration of haematopoiesis. 93 A reduced capacity to defend against pathogens and to initiate adaptive immunity is observed 94 in ageing humans, together with enhanced pro-inflammatory reactions fuelled by 95 ‘endogenous/self-molecular garbage’20, 21. The presence of ‘smouldering’ inflammation in the 96 elderly may aid
Load more

Recommended publications
  • The Clinical Management of Chronic Myelomonocytic Leukemia Eric Padron, MD, Rami Komrokji, and Alan F
    The Clinical Management of Chronic Myelomonocytic Leukemia Eric Padron, MD, Rami Komrokji, and Alan F. List, MD Dr Padron is an assistant member, Dr Abstract: Chronic myelomonocytic leukemia (CMML) is an Komrokji is an associate member, and Dr aggressive malignancy characterized by peripheral monocytosis List is a senior member in the Department and ineffective hematopoiesis. It has been historically classified of Malignant Hematology at the H. Lee as a subtype of the myelodysplastic syndromes (MDSs) but was Moffitt Cancer Center & Research Institute in Tampa, Florida. recently demonstrated to be a distinct entity with a distinct natu- ral history. Nonetheless, clinical practice guidelines for CMML Address correspondence to: have been inferred from studies designed for MDSs. It is impera- Eric Padron, MD tive that clinicians understand which elements of MDS clinical Assistant Member practice are translatable to CMML, including which evidence has Malignant Hematology been generated from CMML-specific studies and which has not. H. Lee Moffitt Cancer Center & Research Institute This allows for an evidence-based approach to the treatment of 12902 Magnolia Drive CMML and identifies knowledge gaps in need of further study in Tampa, Florida 33612 a disease-specific manner. This review discusses the diagnosis, E-mail: [email protected] prognosis, and treatment of CMML, with the task of divorcing aspects of MDS practice that have not been demonstrated to be applicable to CMML and merging those that have been shown to be clinically similar. Introduction Chronic myelomonocytic leukemia (CMML) is a clonal hemato- logic malignancy characterized by absolute peripheral monocytosis, ineffective hematopoiesis, and an increased risk of transformation to acute myeloid leukemia.
    [Show full text]
  • Outcomes for Patients with Chronic Lymphocytic Leukemia and Acute Leukemia Or Myelodysplastic Syndrome
    Leukemia (2016) 30, 325–330 © 2016 Macmillan Publishers Limited All rights reserved 0887-6924/16 www.nature.com/leu ORIGINAL ARTICLE Outcomes for patients with chronic lymphocytic leukemia and acute leukemia or myelodysplastic syndrome FP Tambaro1, G Garcia-Manero2, SM O'Brien2, SH Faderl3, A Ferrajoli2, JA Burger2, S Pierce2, X Wang4, K-A Do4, HM Kantarjian2, MJ Keating2 and WG Wierda2 Acute leukemia (AL) and myelodysplastic syndrome (MDS) are uncommon in chronic lymphocytic leukemia (CLL). We retrospectively identified 95 patients with CLL, also diagnosed with AL (n = 38) or MDS (n = 57), either concurrently (n =5)or subsequent (n = 90) to CLL diagnosis and report their outcomes. Median number of CLL treatments prior to AL and MDS was 2 (0–9) and 1 (0–8), respectively; the most common regimen was purine analog combined with alkylating agent±CD20 monoclonal antibody. Twelve cases had no prior CLL treatment. Among 38 cases with AL, 33 had acute myelogenous leukemia (AML), 3 had acute lymphoid leukemia (ALL; 1 Philadelphia chromosome positive), 1 had biphenotypic and 1 had extramedullary (bladder) AML. Unfavorable AML karyotype was noted in 26, and intermediate risk in 7 patients. There was no association between survival from AL and number of prior CLL regimens or karyotype. Expression of CD7 on blasts was associated with shorter survival. Among MDS cases, all International Prognostic Scoring System (IPSS) were represented; karyotype was unfavorable in 36, intermediate in 6 and favorable in 12 patients; 10 experienced transformation to AML. Shorter survival from MDS correlated with higher risk IPSS, poor-risk karyotype and increased number of prior CLL treatments.
    [Show full text]
  • Myelodysplastic Syndromes Overview and Types
    cancer.org | 1.800.227.2345 About Myelodysplastic Syndromes Overview and Types If you have been diagnosed with a myelodysplastic syndrome or are worried about it, you likely have a lot of questions. Learning some basics is a good place to start. ● What Are Myelodysplastic Syndromes? ● Types of Myelodysplastic Syndromes Research and Statistics See the latest estimates for new cases of myelodysplastic syndromes in the US and what research is currently being done. ● Key Statistics for Myelodysplastic Syndromes ● What's New in Myelodysplastic Syndrome Research? What Are Myelodysplastic Syndromes? Myelodysplastic syndromes (MDS) are conditions that can occur when the blood- forming cells in the bone marrow become abnormal. This leads to low numbers of one or more types of blood cells. MDS is considered a type of cancer1. Normal bone marrow 1 ____________________________________________________________________________________American Cancer Society cancer.org | 1.800.227.2345 Bone marrow is found in the middle of certain bones. It is made up of blood-forming cells, fat cells, and supporting tissues. A small fraction of the blood-forming cells are blood stem cells. Stem cells are needed to make new blood cells. There are 3 main types of blood cells: red blood cells, white blood cells, and platelets. Red blood cells pick up oxygen in the lungs and carry it to the rest of the body. These cells also bring carbon dioxide back to the lungs. Having too few red blood cells is called anemia. It can make a person feel tired and weak and look pale. Severe anemia can cause shortness of breath. White blood cells (also known as leukocytes) are important in defending the body against infection.
    [Show full text]
  • Molecular Profiling of Myeloid Progenitor Cells in Multi-Mutated Advanced Systemic Mastocytosis Identifies KIT D816V As a Distin
    Leukemia (2015) 29, 1115–1122 © 2015 Macmillan Publishers Limited All rights reserved 0887-6924/15 www.nature.com/leu ORIGINAL ARTICLE Molecular profiling of myeloid progenitor cells in multi-mutated advanced systemic mastocytosis identifies KIT D816V as a distinct and late event M Jawhar1,8, J Schwaab1,8, S Schnittger2, K Sotlar3, H-P Horny3, G Metzgeroth1, N Müller1, S Schneider4, N Naumann1, C Walz3, T Haferlach2, P Valent5, W-K Hofmann1, NCP Cross6,7, A Fabarius1 and A Reiter1 To explore the molecular profile and its prognostic implication in systemic mastocytosis (SM), we analyzed the mutation status of granulocyte–macrophage colony-forming progenitor cells (CFU-GM) in patients with KIT D816V+ indolent SM (ISM, n = 4), smoldering SM (SSM, n = 2), aggressive SM (ASM, n = 1), SM with associated clonal hematologic non-mast cell lineage disorder (SM-AHNMD, n = 5) and ASM-AHNMD (n = 7). All patients with (A)SM-AHNMD (n = 12) carried 1–4 (median 3) additional mutations in 11 genes tested, most frequently TET2, SRSF2, ASXL1, CBL and EZH2. In multi-mutated (A)SM-AHNMD, KIT D816V+ single-cell-derived CFU-GM colonies were identified in 8/12 patients (median 60%, range 0–95). Additional mutations were identified in CFU-GM colonies in all patients, and logical hierarchy analysis indicated that mutations in TET2, SRSF2 and ASXL1 preceded KIT D816V. In ISM/SSM, no additional mutations were detected and CFU-GM colonies were exclusively KIT D816V−. These data indicate that (a) (A)SM-AHNMD is a multi-mutated neoplasm, (b) mutations in TET2, SRSF2 or ASXL1 precede KIT D816V in ASM-AHNMD, (c) KIT D816V is thus a phenotype modifier toward SM and (d) KIT D816V or other mutations are rare in CFU-GM colonies of ISM/SSM patients, which might explain at least in part their better prognosis.
    [Show full text]
  • Guidelines for the Diagnosis and Treatment of Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia
    MDS and CMML Guidelines Guidelines for the diagnosis and treatment of Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia Nordic MDS Group 8th update, May 2017 1 MDS and CMML Guidelines WRITING COMMITTEE ................................................................................................................ 4 CONTACT INFORMATION ........................................................................................................... 4 EVIDENCE LEVELS AND RECOMMENDATION GRADES ................................................... 5 DIAGNOSTIC WORKUP OF SUSPECTED MDS ....................................................................... 5 TABLE 2. 2016 REVISION TO THE WHO CLASSIFICATION OF MDS .................................................... 6 TABLE 3. 2016 REVISION TO WHO CLASSIFICATION OF MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS ....................................................................................................................................... 7 PROGNOSIS .................................................................................................................................... 10 IPSS FOR MDS (INTERNATIONAL PROGNOSTIC SCORING SYSTEM) ................................................ 10 REVISED IPSS (IPSS-R) ................................................................................................................. 11 SIMPLIFIED RISK CATEGORIES (IPSS AND IPSS-R) ......................................................................... 11 ADDITIONAL PROGNOSTIC FACTORS ...............................................................................................
    [Show full text]
  • Myelodysplastic Syndrome Early Detection, Diagnosis, and Staging Detection and Diagnosis
    cancer.org | 1.800.227.2345 Myelodysplastic Syndrome Early Detection, Diagnosis, and Staging Detection and Diagnosis Catching cancer early often allows for more treatment options. Some early cancers may have signs and symptoms that can be noticed, but that is not always the case. ● Can Myelodysplastic Syndromes Be Found Early? ● Signs and Symptoms of Myelodysplastic Syndromes ● Tests for Myelodysplastic Syndromes MDS Scores and Prognosis (Outlook) Myelodysplastic syndrome scores provide important information about the anticipated response to treatment. ● Myelodysplastic Syndrome Prognostic Scores ● Survival Statistics for Myelodysplastic Syndromes Questions to Ask About Myelodysplastic Syndromes Here are some questions you can ask your cancer care team to help you better understand your diagnosis and treatment options. ● Questions to Ask Your Doctor About Myelodysplastic Syndromes 1 ____________________________________________________________________________________American Cancer Society cancer.org | 1.800.227.2345 Can Myelodysplastic Syndromes Be Found Early? At this time, there are no widely recommended tests to screen for myelodysplastic syndromes (MDS). (Screening is testing for cancer in people without any symptoms.) MDS is sometimes found when a person sees a doctor because of signs or symptoms they are having. These signs and symptoms often do not show up in the early stages of MDS. But sometimes MDS is found before it causes symptoms because of an abnormal result on a blood test that was done as part of a routine exam or for some other health reason. MDS that is found early does not always need to be treated right away, but it should be watched closely for signs that it's progressing. For some people who are known to be at increased risk1, such as people with certain inherited syndromes or people who have received certain chemotherapy drugs, doctors might recommend close follow-up with blood tests or other exams or tests to look for possible early signs of MDS.
    [Show full text]
  • T-Cell Prolymphocytic Leukemia Accompanied by Plural M-Proteins with Myelodysplastic Syndrome in a Nonagenarian
    ical C lin as C e Saito et al., J Clin Case Rep 2012, 2:7 f R o l e DOI: 10.4172/2165-7920.1000131 a p n o r r t u s o J Journal of Clinical Case Reports ISSN: 2165-7920 Case Report Open Access T-Cell Prolymphocytic Leukemia Accompanied by Plural M-Proteins with Myelodysplastic Syndrome in a Nonagenarian Nagahito Saito1*, Katsuhiro Higashiura1, Kenta Honma1, Shinji Kurosawa1, Kazunori Ehata1, Tomoyuki Yanami1, Katsumi Katagiri1, Hiroyuki Sugiki2 and Hong Kean Ooi3,4* 1Internal Medicine, Nemuro City Hospital, Nemuro, Hokkaido, Japan 2Internal Medicine, Nemuro Kyoritsu Hospital, Nemuro, Hokkaido, Japan 3Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan 4Veterinary Medicine, Yamaguchi University, Japan Abstract T-cell Pro-Lymphocytic Leukemia (T-PLL) is a rare disease caused by malignancy of mature post-thymic T-cell. Myelodysplastic Syndrome (MDS) is caused by abnormal differentiation of myeloid lineage cells resulting in myeloid leukemia. Both of these hematological disorders are frequently diagnosed in elderly persons. Myeloid lineage is believed to be situated at the position far from lymphoid one as it is regarded on a tree diagram about the blood cell maturation. We reported herein a rare case of T-PLL accompanied by plural M-proteins with MDS a nonagenarian. The 96 years old patient was admitted to our hospital because of lymphocytosis and abnormal lymphocytes. From the bone marrow aspirate, biopsy and hematological findings, abnormalities were observed in cells of three different lineages, namely, (i) neutrophils with hypersegmented-nuclei (ii) erythroblasts with nuclear division, large platelets and megakaryoblastic cells, and (iii) reticulum cells with phagocytosed iron in their cytoplasm.
    [Show full text]
  • Genomic Characterization in Triple-Negative Primary Myelofibrosis and Other Myeloid Neoplasms with Bone Marrow Fibrosis
    Annals of Hematology (2019) 98:2319–2328 https://doi.org/10.1007/s00277-019-03766-z ORIGINAL ARTICLE Genomic characterization in triple-negative primary myelofibrosis and other myeloid neoplasms with bone marrow fibrosis Alberto Alvarez-Larrán1 & Mónica López-Guerra2,3 & María Rozman2 & Juan-Gonzalo Correa1 & Juan Carlos Hernández-Boluda4 & Mar Tormo4 & Daniel Martínez2 & Iván Martín4 & Dolors Colomer2,3 & Jordi Esteve1 & Francisco Cervantes1 Received: 3 June 2019 /Accepted: 20 July 2019 /Published online: 8 August 2019 # Springer-Verlag GmbH Germany, part of Springer Nature 2019 Abstract Triple-negative primary myelofibrosis (TN-PMF) and other myeloid neoplasms with associated bone marrow fibrosis such as the myelodysplastic syndromes (MDS-F) or the myelodysplastic/myeloproliferative neoplasms (MDS/MPN-F) are rare entities, often difficult to distinguish from each other. Thirty-four patients previously diagnosed with TN-PMF (n = 14), MDS-F (n = 18), or MDS/MPN-F (n = 2) were included in the present study. After central revision of the bone marrow histology, diagnoses according to the 2016-WHO classification were TN-PMF (n = 6), MDS-F (n =19),andMDS/MPN-F(n = 9), with TN-PMF genotype representing only 4% of a cohort of 141 molecularly annotated PMF. Genomic classification according to next- generation sequencing and cytogenetic study was performed in 28 cases. Median number of mutations was 4 (range 1–7) in cases with TP53 disruption/aneuploidy or with chromatin-spliceosome mutations versus 1 mutation (range 0–2) in other molec- ular subgroups (p < 0.0001). The number of mutations and the molecular classification were better than PMF and MDS con- ventional scoring systems to predict survival and progression to acute leukemia.
    [Show full text]
  • Remitting Activity of Lenalidomide in Treatment-Induced Myelodysplastic Syndrome
    Letters to the Editor 1576 products was significantly higher (greater than 2-fold) than the 2Department of Leukemia, University of Texas MD Anderson morphologic mast cell counts, which suggested the presence of Cancer Center, Houston, TX, USA KIT mutation in non-mast cell components. Table 1 summarizes E-mail: [email protected] the demographics, BM myeloid cell counts, KIT mutation levels and final disease classification. Review of clinical features and References pathological material revealed coexisting AHNMCD in all five discordant cases. Among the remaining 11 cases in which 1 Akin C, Jaffe ES, Raffeld M, Kirshenbaum AS, Daley T, Noel P et al. percentage of mutated KIT PCR product was roughly equal to or An immunohistochemical study of the bone marrow lesions of less than the number of mast cells, three had associated mild systemic mastocytosis: expression of stem cell factor by lesional eosinophilia, two had associated CMML and the rest were mast cells. Am J Clin Pathol 2002; 118: 242–247. morphologically consistent with pure MCDs. There was striking 2 Longley BJ, Tyrrell L, Lu SZ, Ma YS, Langley K, Ding TG et al. female predominance among the pure MCD and MCD with Somatic c-KIT activating mutation in urticaria pigmentosa and isolated eosinophilia cases (9 of 10) compared to the male aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm. Nat Genet 1996; 12: 312–314. predominance in MCD with AHNMCD cases (6/6 male, Po 3 Nagata H, Worobec AS, Oh CK, Chowdhury BA, Tannenbaum S, 0.002). For all 39 patients in the study, KIT mutation was Suzuki Y et al.
    [Show full text]
  • MDS in Adult Patients -Presentation
    Myelodysplastic syndrome Guru Subramanian Guru Murthy MD Assistant professor Medical College of Wisconsin MDS • Clonal hematopoietic disorder - multilineage hematopoietic progenitor • Ineffective hematopoiesis • Dysplasia • Peripheral cytopenias and bone marrow failure • Risk of transformation to AML in 35 to 40% RBC – Carries oxygen in blood WBC – Fights against infection Platelets – prevents bleeding How common is MDS ? :Zeidan AM et al. Blood Rev 2019 Genetic mutations How does it start ? • Series of genetic events over time • Exposure to environmental factors • Genetic predisposition • Prior chemotherapy or radiotherapy • Epigenetic abnormalities • Abnormal DNA repair • Decreased cell death (apoptosis) • Telomerase dysfunction • Overlaps with other disorders such as aplastic anemia, paroxysmal nocturnal hemoglobinuria Issa J. Blood 2013 Young NS. Ann Intern Med. 2002 Symptoms and signs • Asymptomatic • Fatigue • Easy bleeding • Recurrent infections • Fever • Night sweats Anemia Leukopenia Thrombocytopenia -Tiredness -Increased risk of - Increased bleeding -Fatigue infections -Shortness of breath DIAGNOSIS • History and physical exam – symptoms, medications, transfusions • Peripheral blood counts Cytogenetics FISH and smear review • Bone marrow biopsy and aspiration - Bone marrow blasts % - Cytogenetics/FISH - Iron stain - Reticulin stain Cytopenia + >10% dysplastic cells in 1 or more lineages, or MDS 5-19% blasts, or criteria MDS chromosomal abnormality or Specific MDS mutation Vitamin B12/folate deficiency HIV /viral infection Copper deficiency Conditions that mimic Alcohol abuse MDS Medications (methotrexate, azathioprine, recent chemotherapy) Congenital syndromes (Fanconi anemia) Autoimmune conditions (SLE, ITP) How is MDS treated ? Risk stratification Establishing treatment goals Principles of MDS Disease specific agents management Supportive measures Allogeneic stem cell transplantation IPSS R-IPSS RISK WPSS STRATIFICATION Low risk IPSS Approaches to include genomic features IPSS- International prognostic scoring system Greenberg P et al.
    [Show full text]
  • Sideroblastic Anaemia–A Hitherto Unrecognized Cause of Unexplained Anaemia
    Open Access Original Article Sideroblastic Anaemia Pak Armed Forces Med J 2018; 68 (6): 1755-60 SIDEROBLASTIC ANAEMIA–A HITHERTO UNRECOGNIZED CAUSE OF UNEXPLAINED ANAEMIA Kamran Nazir Ahmad, Shawana Kamran*, Tariq Sarfraz**, Khurshid Ali Bangash***, Aniqa Bano*, Farah Bano*** Pakistan Air Force Hospital Islamabad Pakistan, *Shifa International Hospital Islamabad Pakistan, **Army Medical College/National University of Medical Sciences (NUMS) Rawalpindi Pakistan, ***Combined Military Hospital/National University of Medical Sciences (NUMS) Rawalpindi Pakistan ABSTRACT Objective: To assess the clinicopathological heterogeneity of sideroblastic anemia disorders characterized by the presence of ring sideroblasts in the bone marrow. Study Design: Descriptive study. Place and Duration of Study: Study was conducted at department of Pathology, Combined Military Hospital Kharian, from Apr 2014 to Oct 2016. Material and Methods: A total of ten patients diagnosed as having sideroblastic anemia (SA) on cytomorphological basis were included in the study. After clinical examination of the patients, blood samples were analyzed on Sysmex KX21 Haematology analyzer. Blood and bone marrow aspiration slides were stained with leishman’s stain to study red cell morphology and aspects of haematopoiesis. Assessment of iron stores was done using Perl’s staining technique. Data was collected and analyzed using SPSS 16.0 version. Results: Age range of the SA patients varied from 14-65 years and male to female ratio was 1.3:1. Clinical features included weakness, malaise, easy fatigability, fever, bleeding complications, pallor, splenomegaly and syndrome specific features in 2 patients. MCV ranged from 66 fl to 94 fl. Dimorphic red cell morphology which is considered an important feature of SA was not observed in any patient.
    [Show full text]
  • Meningeal Infiltration of Chronic Myelomonocytic Leukemia
    L al of euk rn em u i o a J Rogulj et al., J Leuk 2014, 2:4 Journal of Leukemia DOI: 10.4172/2329-6917.1000147 ISSN: 2329-6917 Case Report Open Access Meningeal Infiltration of Chronic Myelomonocytic Leukemia Inga Mandac Rogulj, Slobodanka Ostojic Kolonic, Delfa Radic Kristo and Ana Planinc-Peraica Department of Hematology, Clinical Hospital Merkur, Croatia *Corresponding author: Inga Mandac Rogulj, Department of Hematology, Clinical Hospital Merkur, Zajceva Street 19, 10 000 Zagreb, Croatia, Tel: +38512253222; E- mail: [email protected] Rec date: Jul 13, 2014, Acc date: Aug 20, 2014; Pub date: Aug 26, 2014 Copyright: © 2014 Inga Mandac Rogulj, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Chronic Myelomonocytic Leukemia (CMML) is a hematologic malignancy considered a subtype of Myelodysplastic Syndrome (MDS)/Myeloproliferative Disease (MPD). According the World Health Organization (WHO) two subtypes of CMML, CMML-1 and CMML-2 are defined depending on the percentage of blasts in Bone Marrow (BM) and Peripheral Blood (PB). The clinical presentation is variable, but the majority of patients present with fatigue, weight loss, fever, night sweats and splenomegaly, less often skin infiltration or serous effusions. Meningeal leukemic involvement is rarely a presenting feature of CMML. We are reporting a case of 67-year old male with central nervous system involvement of CMML. Introduction Case Presentation Chronic Myelomonocytic Leukemia (CMML) is a rare clonal An 67-year old male was admitted to our Hematology Department hematologic disorder, with a heterogeneous clinical and in September 2011 with nonspecific clinical status presentation, and morphological manifestation.
    [Show full text]