myelodysplastic syndrome (MDS)
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Introduction
variable group of disorders with clonal proliferation of multipotential hematopoietic stem cells, with dysplasia & ineffective production of one or more cell lines.
Classification
- also see classification of myelodysplastic syndrome
- refractory cytopenia with unilineage dysplasia (69)*
- dysplasia in single cell line
- < 5% blasts in bone marrow
- refractory anemia with mutilineage dysplasia (33)*
- dysplasia in more than 1 cell lineage
- +/- ringed sideroblasts
- < 5% blasts in bone marrow
- refractory anemia with ringed sideroblasts (69)*
- erythroid dysplasia
- >= 15% ringed sideroblasts
- < 5% blasts in bone marrow
- MDS with isolated 5q deletion (116)*
- increased megakaryocytes with hypolobulated nuclei
- < 5% blasts in bone marrow
- refractory anemia with excess blasts-1 (18)*
- unilineage or multilineage dysplasia
- no Auer rods
- 5-9% blasts in bone marrow
- refractory anemia with excess blasts-2 (10)*
- unilineage or multilineage dysplasia
- 10-19% blasts in bone marrow
- MDS, unclassified
- does not fit other categories (?)*
- < 5% blasts in bone marrow
Etiology
- primary idiopathic MDS
- secondary to chemotherapy with or without radiation[15]
- may occur years to decades after chemotherapy[1]
- inherited defects in DNA repair
- Down syndrome
Epidemiology
Pathology
- clonal disorders of hematopoietic stem cells
- hypercellular bone marrow
- ineffective maturation of hemapoietic precursurs
- pancytopenia (peripheral blood)
Genetics
- most common: monosomy 7, 5q & 7q deletions
- ringed sideroblasts & 5q deletion are good prognostic features[27]
- translocations involving chromosome 11
- translocation t(5;11)(q35;p15.5) generating a NUP98-NSD1 fusion product
- 17p deletion associated with pseudo Pelger-Huet anomaly
- isolated 20p deletion associated with involvement of erythroid cells & megakaryocytes
- chromosome 3 abnormalities associated with abnormal megakaryocytes
- chromosomal translocation t(1;12)(p36.1;p12) MDS2 with ETV6
- chromosomal translocation t(6;8)(q27;p11) FGFR1OP with FGFR1
- chromosomal translocation t(11;20)(p15;q11) TOP1 with NUP98 chromosomal translocation t(2;8)(p23;p11.2) MYST3 with ASXL2 (therapy-related MDS)
- chromosomal translocation t(5;12)(q31;p13) involving ACSL6 with ETV6 (myelodysplastic syndrome with basophilia)
- chromosomal translocation t(1;3)(p36;q21) involving PRDM16
- role for MDS1, PURB
- loss of Y chromosome[1]
Clinical manifestations
- generally NO splenomegaly
- clinical course is variable
- incidental mild anemia that may be stable for years
- rapidly evolving acute leukemia
Laboratory
- complete blood count (CBC)
- depression in one or more lines of peripheral blood cells
- pancytopenia[1]
- MCV generally elevated (macrocytosis)*
- peripheral smear
- myeloid cell aberrations
- immature myeloid cells may be seen
- dysplastic neutophils
- decreased neutrophil segmentation (Pelger-Huet-like anomaly)
- diminished neutrophil granules
- dysplastic erythrocytes
- blasts > 5% associated with progression to AML
- myeloid cell aberrations
- low reticulocyte count for degree of anemia
- bone marrow biopsy & aspirate
- cytogenetic analysis
- normal in aplastic anemia
- often abnormal in MDS
- generally hypercellular marrow
- 10-15% of patients have hypocellular marrow
- dysplastic erythroid precursors[1]
- iron stain
- > 20% blasts in marrow effectively = AML
- < 2% blasts = low risk[1]
- ringed sideroblasts & 5q deletion are good prognostic features[27]
- cytogenetic analysis
- abnormal cytogenetics
- serum erythropoietin before RBC transfusion[7]
- iron studies[7]
- folate in RBC[7]; serum folate, serum vitamin B12[1]
- serum vitamin B6[7]
- see ARUP consult[12]
* antiretroviral drugs can result induce macrocytosis
Diagnostic procedures
- an algorithm[29] to diagnose MDS uses:
- bone marrow biopsy required for diagnosis []
Complications
- bone marrow failure*
- evolution to acute myelocytic leukemia*
- neutrophilic dermatosis: Sweet syndrome[1][17]
* major causes of death[1]
Differential diagnosis
- acute leukemia
- myeloproferative disorder
- nutritional deficiency
Management
- observation for asymptomatic patients with low risk disease[1]
- supportive care
- RBC transfusions for anemia
- platelet transfusions for thrombocytopenia
- GM-CSF or G-CSF for neutropenia & infectious complications
- erythropoietin first line for symptomatic anemia[30]
- benefits 20% of patients with low serum erythropoietin without del(5q)[28]
- benefit for patients without del(5q) with high-normal serum erythropoietin who wish to avoid erythrocyte transfusion[30]
- lenalidomide for transfusion-dependent anemia with del(5q)[28]
- erythopoiesis-stimulating agent failure
- anti-thymocyte globulin +/- cyclosporine
- luspatercept for MDS-RS with ring sideroblasts[28]
- imetelstat (Rytelo) relapsed or refractory myelodysplastic syndrome with transfusion-dependent anemia erythropoiesis-stimulating agent failure[31]
- bone marrow ablation with allogeneic hematopoietic stem cell transplantation
- only curative treatment
- 50% success rate
- only a minority of patients are candidates
- eligible patients are < 60 years of age
- generally, advanced age at diagnosis
- lack of histocompatible sibling donor
- treatment of choice in eligible patients[1][23]
- pyrimidine nucleosides (hypomethylating agents)[1]
- may induce complete remission in some patients
- may reduce transfusion dependence & tranformation into acute myeloid leukemia[1]
- 5-azacytidine improves survival relative to:
- supportive care
- low-dose cytarabine
- intensive chemotherapy[1][14]
- may take up to 6 months for effect
- transfusion support & antibiotics for infections until effect or lack of apparent[1]
- decitabine (associated with appreciable toxicity)
- thalidomide & analogs
- lenalidomide (Revlimid), FDA-approved 2005
- may decrease need for transfusion[9]
- intended specifically for 5q deletion[16]
- thalidomide plus dexamethasone
- lenalidomide (Revlimid), FDA-approved 2005
- experimental therapies:
- interleukins 3, 6, 11
- all-trans retinoic acid
- amifostine
- immunosuppressive drugs:
- antithymocyte globulin: cases with hypocellular marrow, normal cytogenetics early stage disease, predictors of response include lower platelet count & younger age
- cyclosporine: RA subtype
- inhibitors of tumor necrosis factor alpha (etanercept)
- multidrug resistance approaches
- quinine - capable of reverting the MDR phenotype (P-glycoprotein)
- resistant AML approaches (high toxicity & risk)
- topotecan + cytarabine
- FLAG regimen (fludarabine, cytarabine, G-CSF +/- idarubicin)
Prognosis
- International Scoring System[5]
- see international prognostic scoring system for myelodysplastic syndrome
- morphologic predictors (median survival):
- refractory anemia (4.2 yrs)
- refractory anemia with ringed sideroblasts (6.9 yrs)
- refractory anemia with excess blasts (1.5 yrs)
- refractory anemia with excess blasts in transformation (0.6 yrs)
- adverse prognostic factors
- complex cytogenetic abnormalities
- p53 mutations or LOH: associated with complex karyotypic changes & increased tendency to evolve to AML, reduced response to chemotherapy and shorter survival
- CD34 positive staining of bone marrow nucleated cells
- increased expression of Wilms tumor gene
- increased serum beta-2-microglobulin
- comorbidities
- 3 years survival 35%[8]
- stem cells are resistant to therapy, at least in part due to assuming the G0 phase (in contrast to susceptibility of progenitor cells that remain in cycling phases)[11]
More general terms
More specific terms
- acute panmyelosis with myelofibrosis
- chronic myelomonocytic leukemia (CMML)
- refractory anemia (RA)
- refractory anemia with excess blasts (RAEB)
- refractory anemia with excess blasts in transformation (RAEB-T)
- refractory anemia with ringed sideroblasts (RARS)
Additional terms
- alpha-thalassemia myelodysplasia syndrome
- classification of myelodysplastic syndrome
- international prognostic scoring system for myelodysplastic syndrome
- myeloproliferative disorder
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2022.
Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022 - ↑ Schiller G, in: UCLA Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
- ↑ WHO Classification Tumours of Haematopoietic and Lymphoid Tissues. IARC Press 2001
- ↑ Estey & Schrier. Treatment and prognosis of the myelodysplastic syndromes. UpToDate 2004
- ↑ 5.0 5.1 Greenberg P et al International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997 Mar 15;89(6):2079-88. Erratum in: Blood 1998 Feb 1;91(3):1100. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/9058730 <Internet> http://www.bloodjournal.org/cgi/content/full/89/6/2079 http://www.bloodjournal.org/cgi/content/abstract/89/6/2079 erratum Blood 91:1100, 1998. http://www.bloodjournal.org/cgi/content/full/91/3/1100
- ↑ deprecated reference
- ↑ 7.0 7.1 7.2 7.3 7.4 Steensma DP & Bennett JM The myelodysplastic syndromes: diagnosis and treatment Mayo Clin Proc 2006; 81:104 PMID: https://www.ncbi.nlm.nih.gov/pubmed/16438486
- ↑ 8.0 8.1 8.2 Ma X, Does M, Raza A, Mayne ST. Myelodysplastic syndromes: incidence and survival in the United States. Cancer. 2007 Apr 15;109(8):1536-42. PMID: https://www.ncbi.nlm.nih.gov/pubmed/17345612
Ma X Epidemiology of myelodysplastic syndromes. Am J Med. 2012 Jul;125(7 Suppl):S2-5. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/22735748 - ↑ 9.0 9.1 Raza A et al, Phase 2 study of lenalidomide in transfusion-dependent low- risk, and intermediate-1-risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood 2008, 111:86 PMID: https://www.ncbi.nlm.nih.gov/pubmed/17893227
- ↑ 10.0 10.1 Rollison DE et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs. Blood 2008 Jul 1; 112:45. PMID: https://www.ncbi.nlm.nih.gov/pubmed/18443215
- ↑ 11.0 11.1 Tehranchi R et al. Persistent malignant stem cells in del(5q) myelodysplasia in remission. N Engl J Med 2010 Sep 9; 363:1025 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/20825315 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa0912228
- ↑ 12.0 12.1 ARUP Consult: Myelodysplastic Syndromes The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/myelodysplastic-syndromes
ARUP consult: Myeloid Malignancies Mutation Panel by Next Generation Sequencing https://arupconsult.com/ati/myeloid-malignancies-mutation-panel-next-generation-sequencing - ↑ 13.0 13.1 Foran JM, Shammo JM. Clinical presentation, diagnosis, and prognosis of myelodysplastic syndromes. Am J Med 2012; 125 (7 Suppl):S6-S13 PMID: https://www.ncbi.nlm.nih.gov/pubmed/22735753
Wang R, Gross CP, Halene S, Ma X. Comorbidities and survival in a large cohort of patients with newly diagnosed myelodysplastic syndromes. Leuk Res 2009; 33:1594-1598 PMID: https://www.ncbi.nlm.nih.gov/pubmed/19324411 - ↑ 14.0 14.1 Fenaux P, Mufti GJ, Hellstrom-Lindberg E et al Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009 Mar;10(3):223-32 PMID: https://www.ncbi.nlm.nih.gov/pubmed/19230772
- ↑ 15.0 15.1 Borthakur G, Estey AE. Therapy-related acute myelogenous leukemia and myelodysplastic syndrome. Curr Oncol Rep. 2007 Sep;9(5):373-7. PMID: https://www.ncbi.nlm.nih.gov/pubmed/17706165
- ↑ 16.0 16.1 List A, Dewald G, Bennett J, Giagounidis A et al Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006 Oct 5;355(14):1456-65. PMID: https://www.ncbi.nlm.nih.gov/pubmed/17021321
- ↑ 17.0 17.1 Farah C, Bulai Livideanu C, Jegu J et al Prevalence and prognostic value of cutaneous manifestations in patients with myelodysplastic syndrome. J Eur Acad Dermatol Venereol. 2010 Oct;24(10):1171-5. PMID: https://www.ncbi.nlm.nih.gov/pubmed/20202054
- ↑ Estey E. Acute myeloid leukemia and myelodysplastic syndromes in older patients. J Clin Oncol. 2007 May 10;25(14):1908-15. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/17488990
- ↑ Greenberg PL, Tuechler H, Schanz J et al Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012 Sep 20;120(12):2454-65. Epub 2012 Jun 27. PMID: https://www.ncbi.nlm.nih.gov/pubmed/22740453
- ↑ Lyons RM Myelodysplastic syndromes: therapy and outlook. Am J Med. 2012 Jul;125(7 Suppl):S18-23 PMID: https://www.ncbi.nlm.nih.gov/pubmed/22735747
- ↑ Vaughn JE, Scott BL, Deeg HJ. Transplantation for myelodysplastic syndromes 2013. Curr Opin Hematol. 2013 Nov;20(6):494-500 PMID: https://www.ncbi.nlm.nih.gov/pubmed/24104409
- ↑ Michiels JJ, Berneman Z, Schroyens W, De Raeve H. Changing concepts of diagnostic criteria of myeloproliferative disorders and the molecular etiology and classification of myeloproliferative neoplasms: from Dameshek 1950 to Vainchenker 2005 and beyond. Acta Haematol. 2015;133(1):36-51. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/25116092
- ↑ 23.0 23.1 Mufti GJ, Potter V. Myelodysplastic syndromes: who and when in the course of disease to transplant. Hematology Am Soc Hematol Educ Program. 2012;2012:49-55. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/23233560
- ↑ Giagounidis A, Mufti GJ, Mittelman M et al Outcomes in RBC transfusion-dependent patients with Low-/ Intermediate-1-risk myelodysplastic syndromes with isolated deletion 5q treated with lenalidomide: a subset analysis from the MDS-004 study. Eur J Haematol. 2014 Nov;93(5):429-38. Epub 2014 Jun 9. PMID: https://www.ncbi.nlm.nih.gov/pubmed/24813620 Free PMC Article
- ↑ Nolte F, Angelucci E, Breccia M et al Updated recommendations on the management of gastrointestinal disturbances during iron chelation therapy with Deferasirox in transfusion dependent patients with myelodysplastic syndrome - Emphasis on optimized dosing schedules and new formulations. Leuk Res. 2015 Oct;39(10):1028-33. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/26293555
- ↑ Fenaux P, Haase D, Sanz GF et al Myelodysplastic syndromes: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014 Sep;25 Suppl 3:iii57-69. PMID: https://www.ncbi.nlm.nih.gov/pubmed/25185242
- ↑ 27.0 27.1 27.2 Geriatric Review Syllabus, 10th edition (GRS10) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2019
- ↑ 28.0 28.1 28.2 28.3 European Society of Medical Oncology Myelodysplastic Syndromes Clinical Practice Guidelines (ESMO, 2021). Medscape. Feb 3, 2021 https://reference.medscape.com/viewarticle/944879
- ↑ 29.0 29.1 29.2 Oster HS, Crouch S, Smith A et al. A predictive algorithm using clinical and laboratory parameters may assist in ruling out and in diagnosing MDS. Blood Adv 2021 Aug 24; 5:3066-3075 PMID: https://www.ncbi.nlm.nih.gov/pubmed/34387647 https://ashpublications.org/bloodadvances/article/5/16/3066/476533/A-predictive-algorithm-using-clinical-and
- ↑ 30.0 30.1 30.2 NEJM Knowledge+ Hematology
- ↑ 31.0 31.1 Worcester S FDA Approves Imetelstat for Lower-Risk Myelodysplastic Syndromes. Medscape. June 7, 2024 https://www.medscape.com/viewarticle/fda-approves-imetelstat-lower-risk-myelodysplastic-syndromes-2024a1000as3
Platzbecker U, Santini V, Fenaux P et al Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024 Jan 20;403(10423):249-260. PMID: https://www.ncbi.nlm.nih.gov/pubmed/38048786 Clinical Trial. - ↑ Myelodysplastic Syndromes (PDQ): Treatment http://www.nci.nih.gov/cancertopics/pdq/treatment/myelodysplastic/HealthProfessional
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