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Diagnosis of Blood and Bone Marrow Disorders pp 17–79Cite as

Cytopenias: Reactive and Neoplastic

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Abstract

Cytopenias are the most common peripheral blood count abnormality that come to medical attention and, in a subset of cases, stimulate performance of a bone marrow biopsy. Cytopenias encompass anemia, leukopenia (most often reduction of the absolute neutrophil count, but also including monocytopenia and lymphopenia), and thrombocytopenia. They may be isolated, involving only one cell line, or may involve two or all three cell lines (pancytopenia).

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References

  1. Hillman RS, Ault KA, Leporrier M, Rinder HM. Normal erythropoiesis. In: Hematology in clinical practice, vol. 5e. New York: McGraw-Hill Medical; 2016.

    Google Scholar 

  2. Hillman RS, Ault KA, Leporrier M, Rinder HM. Iron-deficiency anemia. In: Hematology in clinical practice, vol. 5e. New York: McGraw-Hill Medical; 2016.

    Google Scholar 

  3. Barrett AN, Saminathan R, Choolani M. Thalassaemia screening and confirmation of carriers in parents. Best Pract Res Clin Obstet Gynaecol. 2017;39:27–40.

    Article  PubMed  Google Scholar 

  4. Hillman RS, Ault KA, Leporrier M, Rinder HM. The dysplastic and sideroblastic anemias. In: Hematology in clinical practice, vol. 5e. New York: McGraw-Hill Medical; 2016.

    Google Scholar 

  5. Bottomley SS, Fleming MD. Sideroblastic anemia: diagnosis and management. Hematol Oncol Clin North Am. 2014;28(4):653–70, v

    Article  PubMed  Google Scholar 

  6. Holbro A, Jauch A, Lardinois D, Tzankov A, Dirnhofer S, Hess C. High prevalence of infections and autoimmunity in patients with thymoma. Hum Immunol. 2012;73(3):287–90.

    Article  PubMed  CAS  Google Scholar 

  7. Go RS, Lust JA, Phyliky RL. Aplastic anemia and pure red cell aplasia associated with large granular lymphocyte leukemia. Semin Hematol. 2003;40(3):196–200.

    Article  PubMed  CAS  Google Scholar 

  8. Young NS, Brown KE. Parvovirus B19. N Engl J Med. 2004;350(6):586–97.

    Article  PubMed  CAS  Google Scholar 

  9. Wolfromm A, Rodriguez C, Michel M, Habibi A, Audard V, Benayoun E, et al. Spectrum of adult Parvovirus B19 infection according to the underlying predisposing condition and proposals for clinical practice. Br J Haematol. 2015;170(2):192–9.

    Article  PubMed  CAS  Google Scholar 

  10. Brown KE. Haematological consequences of parvovirus B19 infection. Bailliere’s Best Pract Res Clin Haematol. 2000;13(2):245–59.

    Article  CAS  Google Scholar 

  11. Young NS. Pure Red Cell Aplasia. In: Kaushansky K, Lichtman MA, Prchal JT, Levi MM, Press OW, Burns LJ, et al., editors. Williams hematology. New York: McGraw-Hill Education; 2015. p. 9e.

    Google Scholar 

  12. Wang SA, Yue G, Hutchinson L, Landry ML, Hasserjian RP, Hao S, et al. Myelodysplastic syndrome with pure red cell aplasia shows characteristic clinicopathological features and clonal T-cell expansion. Br J Haematol. 2007;138(2):271–5.

    Article  PubMed  Google Scholar 

  13. Makoni SN, Laber DA. Clinical spectrum of myelophthisis in cancer patients. Am J Hematol. 2004;76(1):92–3.

    Article  PubMed  Google Scholar 

  14. Paydas S, Ergin M, Baslamisli F, Yavuz S, Zorludemir S, Sahin B, et al. Bone marrow necrosis: clinicopathologic analysis of 20 cases and review of the literature. Am J Hematol. 2002;70(4):300–5.

    Article  PubMed  Google Scholar 

  15. Halil O, Farringdon K. Oxalosis: an unusual cause of leucoerythroblastic anaemia. Br J Haematol. 2003;122(1):2.

    Article  PubMed  Google Scholar 

  16. Reddy VVB, Prchal JT. Anemia Associated with Marrow Infiltration. In: Kaushansky K, Lichtman MA, Prchal JT, Levi MM, Press OW, Burns LJ, et al., editors. Williams hematology. New York: McGraw-Hill Education; 2015. p. 9e.

    Google Scholar 

  17. Kim Y, Park J, Kim M. Diagnostic approaches for inherited hemolytic anemia in the genetic era. Blood Res. 2017;52(2):84–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Narla J, Mohandas N. Red cell membrane disorders. Int J Lab Hematol. 2017;39(Suppl 1):47–52.

    Article  PubMed  Google Scholar 

  19. Gallagher PG. Hereditary elliptocytosis: spectrin and protein 4.1R. Semin Hematol. 2004;41(2):142–64.

    Article  PubMed  CAS  Google Scholar 

  20. Zarkowsky HS, Mohandas N, Speaker CB, Shohet SB. A congenital haemolytic anaemia with thermal sensitivity of the erythrocyte membrane. Br J Haematol. 1975;29(4):537–43.

    Article  PubMed  CAS  Google Scholar 

  21. Coetzer TL. Erythrocyte membrane disorders. In: Kaushansky K, Lichtman MA, Prchal JT, Levi MM, Press OW, Burns LJ, et al., editors. Williams hematology. New York: McGraw-Hill Education; 2015. p. 9e.

    Google Scholar 

  22. van Solinge WW, van Wijk R. Erythrocyte enzyme disorders. In: Kaushansky K, Lichtman MA, Prchal JT, Levi MM, Press OW, Burns LJ, et al., editors. Williams hematology. New York: McGraw-Hill Education; 2015. p. 9e.

    Google Scholar 

  23. LaRue N, Kahn M, Murray M, Leader BT, Bansil P, McGray S, et al. Comparison of quantitative and qualitative tests for glucose-6-phosphate dehydrogenase deficiency. Am J Trop Med Hyg. 2014;91(4):854–61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Mario N, Baudin B, Aussel C, Giboudeau J. Capillary isoelectric focusing and high-performance cation-exchange chromatography compared for qualitative and quantitative analysis of hemoglobin variants. Clin Chem. 1997;43(11):2137–42.

    Article  PubMed  CAS  Google Scholar 

  25. Packman CH. Hemolytic anemia resulting from immune injury. In: Kaushansky K, Lichtman MA, Prchal JT, Levi MM, Press OW, Burns LJ, et al., editors. Williams hematology. New York: McGraw-Hill Education; 2015. p. 9e.

    Google Scholar 

  26. Janka GE. Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr. 1983;140(3):221–30.

    Article  PubMed  CAS  Google Scholar 

  27. Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S, Mathew PA, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science. 1999;286(5446):1957–9.

    Article  PubMed  CAS  Google Scholar 

  28. Zur Stadt U, Beutel K, Kolberg S, Schneppenheim R, Kabisch H, Janka G, et al. Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A. Hum Mutat. 2006;27(1):62–8.

    Article  PubMed  CAS  Google Scholar 

  29. Rouphael NG, Talati NJ, Vaughan C, Cunningham K, Moreira R, Gould C. Infections associated with haemophagocytic syndrome. Lancet Infect Dis. 2007;7(12):814–22.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Dhote R, Simon J, Papo T, Detournay B, Sailler L, Andre MH, et al. Reactive hemophagocytic syndrome in adult systemic disease: report of twenty-six cases and literature review. Arthritis Rheum. 2003;49(5):633–9.

    Article  PubMed  Google Scholar 

  31. Verbsky JW, Grossman WJ. Hemophagocytic lymphohistiocytosis: diagnosis, pathophysiology, treatment, and future perspectives. Ann Med. 2006;38(1):20–31.

    Article  PubMed  CAS  Google Scholar 

  32. Kelesidis T, Humphries R, Terashita D, Eshaghian S, Territo MC, Said J, et al. Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in Los Angeles County. J Med Virol. 2012;84(5):777–85.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Henter JI, Ehrnst A, Andersson J, Elinder G. Familial hemophagocytic lymphohistiocytosis and viral infections. Acta Paediatr. 1993;82(4):369–72.

    Article  PubMed  CAS  Google Scholar 

  34. Clementi R, Emmi L, Maccario R, Liotta F, Moretta L, Danesino C, et al. Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. Blood. 2002;100(6):2266–7.

    Article  PubMed  CAS  Google Scholar 

  35. Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124–31.

    Article  PubMed  Google Scholar 

  36. Risdall RJ, McKenna RW, Nesbit ME, Krivit W, Balfour HH Jr, Simmons RL, et al. Virus-associated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer. 1979;44(3):993–1002.

    Article  PubMed  CAS  Google Scholar 

  37. Filipovich AH. Hemophagocytic lymphohistiocytosis and related disorders. Curr Opin Allergy Clin Immunol. 2006;6(6):410–5.

    Article  PubMed  CAS  Google Scholar 

  38. Ho C, Yao X, Tian L, Li FY, Podoltsev N, Xu ML. Marrow assessment for hemophagocytic lymphohistiocytosis demonstrates poor correlation with disease probability. Am J Clin Pathol. 2014;141(1):62–71.

    Article  PubMed  Google Scholar 

  39. Green R. Folate, Cobalamin, and Megaloblastic Anemias. In: Kaushansky K, Lichtman MA, Prchal JT, Levi MM, Press OW, Burns LJ, et al., editors. Williams hematology. New York: McGraw-Hill Education; 2015. p. 9e.

    Google Scholar 

  40. Dale DC, Welte K. Neutropenia and neutrophilia. In: Kaushansky K, Lichtman MA, Prchal JT, Levi MM, Press OW, Burns LJ, et al., editors. Williams hematology. New York: McGraw-Hill Education; 2015. p. 9e.

    Google Scholar 

  41. Barbosa MD, Nguyen QA, Tchernev VT, Ashley JA, Detter JC, Blaydes SM, et al. Identification of the homologous beige and Chediak-Higashi syndrome genes. Nature. 1996;382(6588):262–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Griscelli C, Durandy A, Guy-Grand D, Daguillard F, Herzog C, Prunieras M. A syndrome associating partial albinism and immunodeficiency. Am J Med. 1978;65(4):691–702.

    Article  PubMed  CAS  Google Scholar 

  43. Hernandez PA, Gorlin RJ, Lukens JN, Taniuchi S, Bohinjec J, Francois F, et al. Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nat Genet. 2003;34(1):70–4.

    Article  PubMed  CAS  Google Scholar 

  44. Dale DC, Link DC. The many causes of severe congenital neutropenia. N Engl J Med. 2009;360(1):3–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Horwitz M, Benson KF, Person RE, Aprikyan AG, Dale DC. Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nat Genet. 1999;23(4):433–6.

    Article  PubMed  CAS  Google Scholar 

  46. Papadaki HA, Palmblad J, Eliopoulos GD. Non-immune chronic idiopathic neutropenia of adult: an overview. Eur J Haematol. 2001;67(1):35–44.

    Article  PubMed  CAS  Google Scholar 

  47. Gregg XT, Reddy V, Prchal JT. Copper deficiency masquerading as myelodysplastic syndrome. Blood. 2002;100(4):1493–5.

    Article  PubMed  CAS  Google Scholar 

  48. Dale DC. How I diagnose and treat neutropenia. Curr Opin Hematol. 2016;23(1):1–4.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Maheshwari A, Christensen RD, Calhoun DA. Immune-mediated neutropenia in the neonate. Acta Paediatr Suppl. 2002;91(438):98–103.

    Article  PubMed  CAS  Google Scholar 

  50. Starkebaum G. Chronic neutropenia associated with autoimmune disease. Semin Hematol. 2002;39(2):121–7.

    Article  PubMed  Google Scholar 

  51. Dale DC. How I manage children with neutropenia. Br J Haematol. 2017;178(3):351–63.

    Article  PubMed  Google Scholar 

  52. Vasu S, Caligiuri MA. Lymphocytosis and Lymphocytopenia. In: Kaushansky K, Lichtman MA, Prchal JT, Levi MM, Press OW, Burns LJ, et al., editors. Williams hematology. New York: McGraw-Hill Education; 2015. p. 9e.

    Google Scholar 

  53. Twomey JJ, Douglass CC, Sharkey O Jr. The monocytopenia of aplastic anemia. Blood. 1973;41(2):187–95.

    Article  PubMed  CAS  Google Scholar 

  54. Viegas LR, Hoijman E, Beato M, Pecci A. Mechanisms involved in tissue-specific apopotosis regulated by glucocorticoids. J Steroid Biochem Mol Biol. 2008;109(3–5):273–8.

    Article  CAS  Google Scholar 

  55. Fauci AS, Dale DC. The effect of in vivo hydrocortisone on subpopulations of human lymphocytes. J Clin Invest. 1974;53(1):240–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Ganapathi KA, Townsley DM, Hsu AP, Arthur DC, Zerbe CS, Cuellar-Rodriguez J, et al. GATA2 deficiency-associated bone marrow disorder differs from idiopathic aplastic anemia. Blood. 2015;125(1):56–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Diz-Küçükkaya R, López JA. Thrombocytopenia. In: Kaushansky K, Lichtman MA, Prchal JT, Levi MM, Press OW, Burns LJ, et al., editors. Williams hematology, vol. 9e. New York: McGraw-Hill Education; 2015.

    Google Scholar 

  58. He R, Reid DM, Jones CE, Shulman NR. Spectrum of Ig classes, specificities, and titers of serum antiglycoproteins in chronic idiopathic thrombocytopenic purpura. Blood. 1994;83(4):1024–32.

    Article  PubMed  CAS  Google Scholar 

  59. Dameshek W, Miller EB. The megakaryocytes in idiopathic thrombocytopenic purpura, a form of hypersplenism. Blood. 1946;1:27–50.

    Article  PubMed  CAS  Google Scholar 

  60. Kuter DJ, Mufti GJ, Bain BJ, Hasserjian RP, Davis W, Rutstein M. Evaluation of bone marrow reticulin formation in chronic immune thrombocytopenia patients treated with romiplostim. Blood. 2009;114(18):3748–56.

    Article  PubMed  CAS  Google Scholar 

  61. Brynes RK, Orazi A, Theodore D, Burgess P, Bailey CK, Thein MM, et al. Evaluation of bone marrow reticulin in patients with chronic immune thrombocytopenia treated with eltrombopag: Data from the EXTEND study. Am J Hematol. 2015;90(7):598–601.

    Article  PubMed  CAS  Google Scholar 

  62. Arepally GM. Heparin-induced thrombocytopenia. Blood. 2017;129(21):2864–72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Bulchandani D, Nachnani J, Belt R, Hinton S. Acquired pure megakaryocytic aplasia: report of a single case treated with mycophenolate mofetil. Am J Hematol. 2007;82(7):650–1.

    Article  PubMed  Google Scholar 

  64. Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120(12):2454–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114(5):937–51.

    Article  PubMed  CAS  Google Scholar 

  66. Garand R, Goasguen J, Brizard A, Buisine J, Charpentier A, Claisse JF, et al. Indolent course as a relatively frequent presentation in T-prolymphocytic leukaemia. Groupe Francais d’Hematologie Cellulaire. Br J Haematol. 1998;103(2):488–94.

    Article  CAS  PubMed  Google Scholar 

  67. Forty-five Years of Cancer Incidence in Connecticut, 1935–79. Washington, DC: US Government Printing Office; 1986.

    Google Scholar 

  68. Cartwright RA, McNally RJQ, Rowland DJ, Thomas J. The descriptive epidemiology of leukaemia and related conditions in parts of the United Kingdom, 1984–1993. London: Leukemia Research Fund; 1997.

    Google Scholar 

  69. Germing U, Strupp C, Kundgen A, Bowen D, Aul C, Haas R, et al. No increase in age-specific incidence of myelodysplastic syndromes. Haematologica. 2004;89(8):905–10.

    PubMed  Google Scholar 

  70. Schoch C, Schnittger S, Kern W, Dugas M, Hiddemann W, Haferlach T. Acute myeloid leukemia with recurring chromosome abnormalities as defined by the WHO-classification: incidence of subgroups, additional genetic abnormalities, FAB subtypes and age distribution in an unselected series of 1,897 patients with acute myeloid leukemia. Haematologica. 2003;88(3):351–2.

    PubMed  Google Scholar 

  71. Smith MT, Linet MS, Morgan GJ. Causative agents in the etiology of myelodysplastic syndromes and the acute myeloid leukemias. In: Bennett JM, editor. The myelodysplastic syndromes, pathobiology and clinical management. New York: Marcel Dekker; 2002. p. 29–63.

    Google Scholar 

  72. Ma X, Does M, Raza A, Mayne ST. Myelodysplastic syndromes: incidence and survival in the United States. Cancer. 2007;109(8):1536–42.

    Article  PubMed  Google Scholar 

  73. Hasle H, Wadsworth LD, Massing BG, McBride M, Schultz KR. A population-based study of childhood myelodysplastic syndrome in British Columbia, Canada. Br J Haematol. 1999;106(4):1027–32.

    Article  PubMed  CAS  Google Scholar 

  74. Passmore SJ, Chessells JM, Kempski H, Hann IM, Brownbill PA, Stiller CA. Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia in the UK: a population-based study of incidence and survival. Br J Haematol. 2003;121(5):758–67.

    Article  PubMed  Google Scholar 

  75. Rollison DE, Howlader N, Smith MT, Strom SS, Merritt WD, Ries LA, 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;112(1):45–52.

    Article  PubMed  CAS  Google Scholar 

  76. Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126(1):9–16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Gyan E, Dreyfus F, Fenaux P. Refractory thrombocytopenia and neutropenia: a diagnostic challenge. Mediterr J Hematol Infect Dis. 2015;7(1):e2015018.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Marinier DE, Mesa H, Rawal A, Gupta P. Refractory cytopenias with unilineage dysplasia: a retrospective analysis of refractory neutropenia and refractory thrombocytopenia. Leuk Lymphoma. 2010;51(10):1923–6.

    Article  PubMed  Google Scholar 

  79. Hertenstein B, Kurrle E, Redenbacher M, Arnold R, Heimpel H. Pseudoreticulocytosis in a patient with myelodysplasia. Ann Hematol. 1993;67(3):127–8.

    Article  PubMed  CAS  Google Scholar 

  80. Cohen PR, Talpaz M, Kurzrock R. Malignancy-associated Sweet’s syndrome: review of the world literature. J Clin Oncol. 1988;6(12):1887–97.

    Article  PubMed  CAS  Google Scholar 

  81. Mast K, Taub J, Mosse CA, Matthew P, Hitzler J, Alonzo T, et al. Morphology of myelooid leukemia of down syndrome. Mod Pathol [Abstr]. 2013;26(Suppl 2):345A.

    Google Scholar 

  82. Brunning RD, McKenna RW. Atlas of tumor pathology: tumors of the bone marrow. Washington, DC: Armed Forces Institute of Pathology; 1994.

    Google Scholar 

  83. Foucar K. Bone marrow pathology. 2nd ed. Chicago: ASCP; 2001.

    Google Scholar 

  84. Naeim F. Atlas of bone marrow and blood pathology. Philadelphia: W.B. Saunders; 2001.

    Google Scholar 

  85. Baumann I, Fuhrer M, Behrendt S, Campr V, Csomor J, Furlan I, et al. Morphological differentiation of severe aplastic anaemia from hypocellular refractory cytopenia of childhood: reproducibility of histopathological diagnostic criteria. Histopathology. 2012;61(1):10–7.

    Article  PubMed  Google Scholar 

  86. de Planque MM, Kluin-Nelemans HC, van Krieken HJ, Kluin PM, Brand A, Beverstock GC, et al. Evolution of acquired severe aplastic anaemia to myelodysplasia and subsequent leukaemia in adults. Br J Haematol. 1988;70(1):55–62.

    Article  PubMed  Google Scholar 

  87. Orazi A, Albitar M, Heerema NA, Haskins S, Neiman RS. Hypoplastic myelodysplastic syndromes can be distinguished from acquired aplastic anemia by CD34 and PCNA immunostaining of bone marrow biopsy specimens. Am J Clin Pathol. 1997;107(3):268–74.

    Article  CAS  PubMed  Google Scholar 

  88. Willis MS, McKenna RW, Peterson LC, Coad JE, Kroft SH. Low blast count myeloid disorders with Auer rods: a clinicopathologic analysis of 9 cases. Am J Clin Pathol. 2005;124(2):191–8.

    Article  PubMed  Google Scholar 

  89. Della Porta MG, Travaglino E, Boveri E, Ponzoni M, Malcovati L, Papaemmanuil E, et al. Minimal morphological criteria for defining bone marrow dysplasia: a basis for clinical implementation of WHO classification of myelodysplastic syndromes. Leukemia. 2014;29(1):66–75.

    Article  PubMed  CAS  Google Scholar 

  90. Senent L, Arenillas L, Luno E, Ruiz JC, Sanz G, Florensa L. Reproducibility of the World Health Organization 2008 criteria for myelodysplastic syndromes. Haematologica. 2013;98(4):568–75.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Brunning RD, Orazi A, Germing U, Le Beau MM, Porwit A, Baumann I, et al. Myelodysplastic syndromes/neoplasms, overview. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Piler SA, Stein H, et al., editors. Who classification of tumours of haematopoietic and lymphoid tissues. Lyon: International Agency for Research on Cancer; 2008. p. 88–93.

    Google Scholar 

  92. Bain BJ. The bone marrow aspirate of healthy subjects. Br J Haematol. 1996;94(1):206–9.

    Article  PubMed  CAS  Google Scholar 

  93. Parmentier S, Schetelig J, Lorenz K, Kramer M, Ireland R, Schuler U, et al. Assessment of dysplastic hematopoiesis: lessons from healthy bone marrow donors. Haematologica. 2012;97(5):723–30.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Steensma DP. Dysplasia has a differential diagnosis: distinguishing genuine myelodysplastic syndromes (MDS) from mimics, imitators, copycats and impostors. Curr Hematol Malig Rep. 2012;7(4):310–20.

    Article  PubMed  Google Scholar 

  95. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405.

    Article  PubMed  CAS  Google Scholar 

  96. Germing U, Strupp C, Giagounidis A, Haas R, Gattermann N, Starke C, et al. Evaluation of dysplasia through detailed cytomorphology in 3156 patients from the Dusseldorf Registry on myelodysplastic syndromes. Leuk Res. 2012;36(6):727–34.

    Article  PubMed  Google Scholar 

  97. Maassen A, Strupp C, Giagounidis A, Kuendgen A, Nachtkamp K, Hildebrandt B, et al. Validation and proposals for a refinement of the WHO 2008 classification of myelodysplastic syndromes without excess of blasts. Leuk Res. 2013;37(1):64–70.

    Article  PubMed  Google Scholar 

  98. Verburgh E, Achten R, Louw VJ, Brusselmans C, Delforge M, Boogaerts M, et al. A new disease categorization of low-grade myelodysplastic syndromes based on the expression of cytopenia and dysplasia in one versus more than one lineage improves on the WHO classification. Leukemia. 2007;21(4):668–77.

    Article  PubMed  CAS  Google Scholar 

  99. Hasserjian R, Gattermann N, Bennett JM, Brunning RD, Thiele J. Refractory anaemia with ring sideroblasts. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri S, Stein H, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: International Agency for Research on Cancer; 2008. p. 96–7.

    Google Scholar 

  100. Malcovati L, Hellstrom-Lindberg E, Bowen D, Ades L, Cermak J, Del Canizo C, et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood. 2013;122(17):2943–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Germing U, Strupp C, Kuendgen A, Isa S, Knipp S, Hildebrandt B, et al. Prospective validation of the WHO proposals for the classification of myelodysplastic syndromes. Haematologica. 2006;91(12):1596–604.

    PubMed  Google Scholar 

  102. Malcovati L, Porta MG, Pascutto C, Invernizzi R, Boni M, Travaglino E, et al. Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making. J Clin Oncol. 2005;23(30):7594–603.

    Article  PubMed  Google Scholar 

  103. Malcovati L, Karimi M, Papaemmanuil E, Ambaglio I, Jadersten M, Jansson M, et al. SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts. Blood. 2015;126(2):233–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Brunning RD, Hasserjian RP, Porwit A, Bennett JM, Orazi A, Thiele J, et al. Refractory cytopenia with unilineage dysplasia. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: International Agency for Research on Cancer; 2008. p. 94–5.

    Google Scholar 

  105. Cermak J, Michalova K, Brezinova J, Zemanova Z. A prognostic impact of separation of refractory cytopenia with multilineage dysplasia and 5q- syndrome from refractory anemia in primary myelodysplastic syndrome. Leuk Res. 2003;27(3):221–9.

    Article  PubMed  Google Scholar 

  106. Howe RB, Porwit-MacDonald A, Wanat R, Tehranchi R, Hellstrom-Lindberg E. The WHO classification of MDS does make a difference. Blood. 2004;103(9):3265–70.

    Article  CAS  PubMed  Google Scholar 

  107. Lee JH, Shin YR, Lee JS, Kim WK, Chi HS, Park CJ, et al. Application of different prognostic scoring systems and comparison of the FAB and WHO classifications in Korean patients with myelodysplastic syndrome. Leukemia. 2003;17(2):305–13.

    Article  PubMed  Google Scholar 

  108. Orazi A, Brunning RD, Baumann I, Hasserjian R. Myelodysplastic syndrome, unclassifiable. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri S, Stein H, et al., editors. Who classification of tumours of haematopoietic and lymphoid tissues. Lyon: International Agency for Research on Cancer; 2008. p. 103.

    Google Scholar 

  109. Knipp S, Strupp C, Gattermann N, Hildebrandt B, Schapira M, Giagounidis A, et al. Presence of peripheral blasts in refractory anemia and refractory cytopenia with multilineage dysplasia predicts an unfavourable outcome. Leuk Res. 2008;32(1):33–7.

    Article  PubMed  Google Scholar 

  110. Amin HM, Yang Y, Shen Y, Estey EH, Giles FJ, Pierce SA, et al. Having a higher blast percentage in circulation than bone marrow: clinical implications in myelodysplastic syndrome and acute lymphoid and myeloid leukemias. Leukemia. 2005;19(9):1567–72.

    Article  PubMed  CAS  Google Scholar 

  111. Valent P, Orazi A, Busche G, Schmitt-Graff A, George TI, Sotlar K, et al. Standards and impact of hematopathology in myelodysplastic syndromes (MDS). Oncotarget. 2010;1(7):483–96.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Orazi A, Brunning RD, Hasserjian R, Germing U, Thiele J. Refractory anaemia with excess blasts. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri S, Stein H, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: International Agency for Research on Cancer; 2008. p. 100–1.

    Google Scholar 

  113. Hasle H, Niemeyer CM, Chessells JM, Baumann I, Bennett JM, Kerndrup G, et al. A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases. Leukemia. 2003;17(2):277–82.

    Article  PubMed  CAS  Google Scholar 

  114. Chan GC, Head DR, Wang WC. Refractory anemia with ringed sideroblasts in children: two diseases with a similar phenotype? J Pediatr Hematol Oncol. 1999;21(5):418–23.

    Article  PubMed  CAS  Google Scholar 

  115. Vardiman JW, Arber DA, Brunning RD, Larson RA, Matutes I, Baumann I, et al. Therapy-related myeloid neoplasms. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri S, Stein H, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: International Agency for Research on Cancer; 2008. p. 127–9.

    Google Scholar 

  116. Dann EJ, Rowe JM. Biology and therapy of secondary leukaemias. Best Pract Res Clin Haematol. 2001;14(1):119–37.

    Article  PubMed  CAS  Google Scholar 

  117. Smith SM, Le Beau MM, Huo D, Karrison T, Sobecks RM, Anastasi J, et al. Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series. Blood. 2003;102(1):43–52.

    Article  PubMed  CAS  Google Scholar 

  118. Wong TN, Ramsingh G, Young AL, Miller CA, Touma W, Welch JS, et al. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature. 2015;518(7540):552–5.

    Article  PubMed  CAS  Google Scholar 

  119. Ok CY, Hasserjian RP, Fox PS, Stingo F, Zuo Z, Young KH, et al. Application of the international prognostic scoring system-revised in therapy-related myelodysplastic syndromes and oligoblastic acute myeloid leukemia. Leukemia. 2013;28(1):185–9.

    Article  PubMed  CAS  Google Scholar 

  120. Marisavljevic D, Cemerikic V, Rolovic Z, Boskovic D, Colovic M. Hypocellular myelodysplastic syndromes: clinical and biological significance. Med Oncol. 2005;22(2):169–75.

    Article  PubMed  Google Scholar 

  121. Tuzuner N, Cox C, Rowe JM, Watrous D, Bennett JM. Hypocellular myelodysplastic syndromes (MDS): new proposals. Br J Haematol. 1995;91(3):612–7.

    Article  PubMed  CAS  Google Scholar 

  122. Mikhailova N, Sessarego M, Fugazza G, Caimo A, De Filippi S, van Lint MT, et al. Cytogenetic abnormalities in patients with severe aplastic anemia. Haematologica. 1996;81(5):418–22.

    CAS  PubMed  Google Scholar 

  123. Biesma DH, van den Tweel JG, Verdonck LF. Immunosuppressive therapy for hypoplastic myelodysplastic syndrome. Cancer. 1997;79(8):1548–51.

    Article  PubMed  CAS  Google Scholar 

  124. Lim ZY, Killick S, Germing U, Cavenagh J, Culligan D, Bacigalupo A, et al. Low IPSS score and bone marrow hypocellularity in MDS patients predict hematological responses to antithymocyte globulin. Leukemia. 2007;21(7):1436–41.

    Article  PubMed  CAS  Google Scholar 

  125. Sloand EM, CO W, Greenberg P, Young N, Barrett J. Factors affecting response and survival in patients with myelodysplasia treated with immunosuppressive therapy. J Clin Oncol. 2008;26(15):2505–11.

    Article  PubMed  Google Scholar 

  126. Wang SA, Tang G, Fadare O, Hao S, Raza A, Woda BA, et al. Erythroid-predominant myelodysplastic syndromes: enumeration of blasts from nonerythroid rather than total marrow cells provides superior risk stratification. Mod Pathol. 2008;21(11):1394–402.

    Article  PubMed  Google Scholar 

  127. Bacher U, Haferlach C, Alpermann T, Kern W, Schnittger S, Haferlach T. Comparison of genetic and clinical aspects in patients with acute myeloid leukemia and myelodysplastic syndromes all with more than 50% of bone marrow erythropoietic cells. Haematologica. 2011;96(9):1284–92.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Hasserjian RP, Zuo Z, Garcia C, Tang G, Kasyan A, Luthra R, et al. Acute erythroid leukemia: a reassessment using criteria refined in the 2008 WHO classification. Blood. 2009;115(10):1985–92.

    Article  PubMed  CAS  Google Scholar 

  129. Mazzella FM, Kowal-Vern A, Shrit MA, Wibowo AL, Rector JT, Cotelingam JD, et al. Acute erythroleukemia: evaluation of 48 cases with reference to classification, cell proliferation, cytogenetics, and prognosis. Am J Clin Pathol. 1998;110(5):590–8.

    Article  PubMed  CAS  Google Scholar 

  130. Imbert M, Nguyen D, Sultan C. Myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML) with myelofibrosis. Leuk Res. 1992;16(1):51–4.

    Article  PubMed  CAS  Google Scholar 

  131. Lambertenghi-Deliliers G, Orazi A, Luksch R, Annaloro C, Soligo D. Myelodysplastic syndrome with increased marrow fibrosis: a distinct clinico-pathological entity. Br J Haematol. 1991;78(2):161–6.

    Article  PubMed  CAS  Google Scholar 

  132. Fu B, Jaso JM, Sargent RL, Goswami M, Verstovsek S, Medeiros LJ, et al. Bone marrow fibrosis in patients with primary myelodysplastic syndromes has prognostic value using current therapies and new risk stratification systems. Mod Pathol. 2013;27(5):681–9.

    Article  PubMed  Google Scholar 

  133. Kussick SJ, Fromm JR, Rossini A, Li Y, Chang A, Norwood TH, et al. Four-color flow cytometry shows strong concordance with bone marrow morphology and cytogenetics in the evaluation for myelodysplasia. Am J Clin Pathol. 2005;124(2):170–81.

    Article  PubMed  Google Scholar 

  134. Kern W, Haferlach C, Schnittger S, Haferlach T. Clinical utility of multiparameter flow cytometry in the diagnosis of 1013 patients with suspected myelodysplastic syndrome: correlation to cytomorphology, cytogenetics, and clinical data. Cancer. 2010;116(19):4549–63.

    Article  PubMed  Google Scholar 

  135. van de Loosdrecht AA, Ireland R, Kern W, Della Porta MG, Alhan C, Balleisen JS, et al. Rationale for the clinical application of flow cytometry in patients with myelodysplastic syndromes: position paper of an International Consortium and the European LeukemiaNet Working Group. Leuk Lymphoma. 2012;54(3):472–5.

    Article  PubMed  Google Scholar 

  136. Wells DA, Benesch M, Loken MR, Vallejo C, Myerson D, Leisenring WM, et al. Myeloid and monocytic dyspoiesis as determined by flow cytometric scoring in myelodysplastic syndrome correlates with the IPSS and with outcome after hematopoietic stem cell transplantation. Blood. 2003;102(1):394–403.

    Article  PubMed  CAS  Google Scholar 

  137. Stachurski D, Smith BR, Pozdnyakova O, Andersen M, Xiao Z, Raza A, et al. Flow cytometric analysis of myelomonocytic cells by a pattern recognition approach is sensitive and specific in diagnosing myelodysplastic syndrome and related marrow diseases: emphasis on a global evaluation and recognition of diagnostic pitfalls. Leuk Res. 2008;32(2):215–24.

    Article  PubMed  Google Scholar 

  138. Bellos F, Alpermann T, Gouberman E, Haferlach C, Schnittger S, Haferlach T, et al. Evaluation of flow cytometric assessment of myeloid nuclear differentiation antigen expression as a diagnostic marker for myelodysplastic syndromes in a series of 269 patients. Cytometry B Clin Cytom. 2012;82(5):295–304.

    Article  PubMed  Google Scholar 

  139. McClintock-Treep SA, Briggs RC, Shults KE, Flye-Blakemore LA, Mosse CA, Jagasia MH, et al. Quantitative assessment of myeloid nuclear differentiation antigen distinguishes myelodysplastic syndrome from normal bone marrow. Am J Clin Pathol. 2011;135(3):380–5.

    Article  PubMed  Google Scholar 

  140. Ogata K, Kishikawa Y, Satoh C, Tamura H, Dan K, Hayashi A. Diagnostic application of flow cytometric characteristics of CD34+ cells in low-grade myelodysplastic syndromes. Blood. 2006;108(3):1037–44.

    Article  PubMed  CAS  Google Scholar 

  141. van de Loosdrecht AA, Alhan C, Bene MC, Della Porta MG, Drager AM, Feuillard J, et al. Standardization of flow cytometry in myelodysplastic syndromes: report from the first European LeukemiaNet working conference on flow cytometry in myelodysplastic syndromes. Haematologica. 2009;94(8):1124–34.

    Article  PubMed  PubMed Central  Google Scholar 

  142. Westers TM, Ireland R, Kern W, Alhan C, Balleisen JS, Bettelheim P, et al. Standardization of flow cytometry in myelodysplastic syndromes: a report from an international consortium and the European LeukemiaNet Working Group. Leukemia. 2012;26(7):1730–41.

    Article  CAS  PubMed  Google Scholar 

  143. Kern W, Haferlach C, Schnittger S, Alpermann T, Haferlach T. Serial assessment of suspected myelodysplastic syndromes: significance of flow cytometric findings validated by cytomorphology, cytogenetics, and molecular genetics. Haematologica. 2013;98(2):201–7.

    Article  PubMed  PubMed Central  Google Scholar 

  144. Ogata K, Della Porta MG, Malcovati L, Picone C, Yokose N, Matsuda A, et al. Diagnostic utility of flow cytometry in low-grade myelodysplastic syndromes: a prospective validation study. Haematologica. 2009;94(8):1066–74.

    Article  PubMed  PubMed Central  Google Scholar 

  145. Truong F, Smith BR, Stachurski D, Cerny J, Medeiros LJ, Woda BA, et al. The utility of flow cytometric immunophenotyping in cytopenic patients with a non-diagnostic bone marrow: a prospective study. Leuk Res. 2009;33(8):1039–46.

    Article  PubMed  Google Scholar 

  146. Cleven AH, Nardi V, Ok CY, Goswami M, Dal Cin P, Zheng Z, et al. High p53 protein expression in therapy-related myeloid neoplasms is associated with adverse karyotype and poor outcome. Mod Pathol. 2015;28(4):552–63.

    Article  PubMed  CAS  Google Scholar 

  147. Zhou Y, Tang G, Medeiros LJ, McDonnell TJ, Keating MJ, Wierda WG, et al. Therapy-related myeloid neoplasms following fludarabine, cyclophosphamide, and rituximab (FCR) treatment in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. Mod Pathol. 2012;25(2):237–45.

    Article  PubMed  CAS  Google Scholar 

  148. Seegmiller AC, Wasserman A, Kim AS, Kressin MK, Marx ER, Zutter MM, et al. Limited utility of fluorescence in situ hybridization for common abnormalities of myelodysplastic syndrome at first presentation and follow-up of myeloid neoplasms. Leuk Lymphoma. 2013;55(3):601–5.

    Article  PubMed  CAS  Google Scholar 

  149. Yang W, Stotler B, Sevilla DW, Emmons FN, Murty VV, Alobeid B, et al. FISH analysis in addition to G-band karyotyping: utility in evaluation of myelodysplastic syndromes? Leuk Res. 2010;34(4):420–5.

    Article  PubMed  CAS  Google Scholar 

  150. Vallespi T, Imbert M, Mecucci C, Preudhomme C, Fenaux P. Diagnosis, classification, and cytogenetics of myelodysplastic syndromes. Haematologica. 1998;83(3):258–75.

    PubMed  CAS  Google Scholar 

  151. Olney HJ, Le Beau MM. The cytogenetics and molecular biology of myelodysplastic syndromes. In: Bennett JM, editor. The myelodysplastic syndromes, pathobiology and clinical management. New York: Marcel Dekker; 2002. p. 89–119.

    Google Scholar 

  152. Raimondi SC. Cytogenetics in MDS. In: Lopes LFHH, editor. Myelodysplastic and myeloproliferative disorders in children. Sao Paulo: Le Mar; 2003. p. 119–61.

    Google Scholar 

  153. Gupta V, Brooker C, Tooze JA, Yi QL, Sage D, Turner D, et al. Clinical relevance of cytogenetic abnormalities at diagnosis of acquired aplastic anaemia in adults. Br J Haematol. 2006;134(1):95–9.

    Article  PubMed  CAS  Google Scholar 

  154. Jacobs KB, Yeager M, Zhou W, Wacholder S, Wang Z, Rodriguez-Santiago B, et al. Detectable clonal mosaicism and its relationship to aging and cancer. Nat Genet. 2012;44(6):651–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Soupir CP, Vergilio JA, Kelly E, Dal Cin P, Kuter D, Hasserjian RP. Identification of del(20q) in a subset of patients diagnosed with idiopathic thrombocytopenic purpura. Br J Haematol. 2009;144(5):800–2.

    Article  PubMed  Google Scholar 

  156. Woll PS, Kjallquist U, Chowdhury O, Doolittle H, Wedge DC, Thongjuea S, et al. Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo. Cancer Cell. 2014;25(6):794–808.

    Article  PubMed  CAS  Google Scholar 

  157. Mallo M, Cervera J, Schanz J, Such E, Garcia-Manero G, Luno E, et al. Impact of adjunct cytogenetic abnormalities for prognostic stratification in patients with myelodysplastic syndrome and deletion 5q. Leukemia. 2010;25(1):110–20.

    Article  PubMed  CAS  Google Scholar 

  158. Schanz J, Tuchler H, Sole F, Mallo M, Luno E, Cervera J, et al. New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge. J Clin Oncol. 2012;30(8):820–9.

    Article  PubMed  PubMed Central  Google Scholar 

  159. Morishita K, Parganas E, William CL, Whittaker MH, Drabkin H, Oval J, et al. Activation of EVI1 gene expression in human acute myelogenous leukemias by translocations spanning 300-400 kilobases on chromosome band 3q26. Proc Natl Acad Sci U S A. 1992;89(9):3937–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Rogers HJ, Vardiman JW, Anastasi J, Raca G, Savage NM, Cherry AM, et al. Complex or monosomal karyotype and not blast percentage is associated with poor survival in acute myeloid leukemia and myelodysplastic syndrome patients with inv(3)(q21q26.2)/t(3;3)(q21;q26.2): a Bone Marrow Pathology Group study. Haematologica. 2014;99(5):821–9.

    Article  PubMed  PubMed Central  Google Scholar 

  161. Padua RA, Guinn BA, Al-Sabah AI, Smith M, Taylor C, Pettersson T, et al. RAS, FMS and p53 mutations and poor clinical outcome in myelodysplasias: a 10-year follow-up. Leukemia. 1998;12(6):887–92.

    Article  PubMed  CAS  Google Scholar 

  162. Kanagal-Shamanna R, Bueso-Ramos CE, Barkoh B, Lu G, Wang S, Garcia-Manero G, et al. Myeloid neoplasms with isolated isochromosome 17q represent a clinicopathologic entity associated with myelodysplastic/myeloproliferative features, a high risk of leukemic transformation, and wild-type TP53. Cancer. 2012;118(11):2879–88.

    Article  PubMed  CAS  Google Scholar 

  163. Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature. 2011;478(7367):64–9.

    Article  CAS  PubMed  Google Scholar 

  164. Walter MJ, Shen D, Ding L, Shao J, Koboldt DC, Chen K, et al. Clonal architecture of secondary acute myeloid leukemia. N Engl J Med. 2012;366(12):1090–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Cazzola M, Rossi M, Malcovati L. Biologic and clinical significance of somatic mutations of SF3B1 in myeloid and lymphoid neoplasms. Blood. 2012;121(2):260–9.

    Article  PubMed  CAS  Google Scholar 

  166. Gerstung M, Pellagatti A, Malcovati L, Giagounidis A, Porta MG, Jadersten M, et al. Combining gene mutation with gene expression data improves outcome prediction in myelodysplastic syndromes. Nat Commun. 2015;6:5901.

    Article  PubMed  CAS  Google Scholar 

  167. Papaemmanuil E, Cazzola M, Boultwood J, Malcovati L, Vyas P, Bowen D, et al. Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med. 2011;365(15):1384–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Bejar R, Stevenson KE, Caughey B, Lindsley RC, Mar BG, Stojanov P, et al. Somatic mutations predict poor outcome in patients with myelodysplastic syndrome after hematopoietic stem-cell transplantation. J Clin Oncol. 2014;32(25):2691–8.

    Article  PubMed  PubMed Central  Google Scholar 

  169. Davies SM, Robison LL, Buckley JD, Radloff GA, Ross JA, Perentesis JP. Glutathione S-transferase polymorphisms in children with myeloid leukemia: a Children’s Cancer Group study. Cancer Epidemiol Biomarkers Prev. 2000;9(6):563–6.

    PubMed  CAS  Google Scholar 

  170. Kishi S, Yang W, Boureau B, Morand S, Das S, Chen P, et al. Effects of prednisone and genetic polymorphisms on etoposide disposition in children with acute lymphoblastic leukemia. Blood. 2004;103(1):67–72.

    Article  PubMed  CAS  Google Scholar 

  171. Pui CH, Relling MV, Evans WE. Role of pharmacogenomics and pharmacodynamics in the treatment of acute lymphoblastic leukaemia. Best Pract Res Clin Haematol. 2002;15(4):741–56.

    Article  PubMed  CAS  Google Scholar 

  172. Tang G, Jorgensen LJ, Zhou Y, Hu Y, Kersh M, Garcia-Manero G, et al. Multi-color CD34(+) progenitor-focused flow cytometric assay in evaluation of myelodysplastic syndromes in patients with post cancer therapy cytopenia. Leuk Res. 2012g;36(8):974–81.

    Article  PubMed  Google Scholar 

  173. Ramadurai J, Shapiro C, Kozloff M, Telfer M. Zinc abuse and sideroblastic anemia. Am J Hematol. 1993;42(2):227–8.

    Article  PubMed  CAS  Google Scholar 

  174. Prodan CI, Holland NR, Wisdom PJ, Burstein SA, Bottomley SS. CNS demyelination associated with copper deficiency and hyperzincemia. Neurology. 2002;59(9):1453–6.

    Article  PubMed  CAS  Google Scholar 

  175. Condamine L, Hermine O, Alvin P, Levine M, Rey C, Courtecuisse V. Acquired sideroblastic anaemia during treatment of Wilson's disease with triethylene tetramine dihydrochloride. Br J Haematol. 1993;83(1):166–8.

    Article  PubMed  CAS  Google Scholar 

  176. Dunlap WM, James GW 3rd, Hume DM. Anemia and neutropenia caused by copper deficiency. Ann Intern Med. 1974;80(4):470–6.

    Article  PubMed  CAS  Google Scholar 

  177. Rezuke WN, Anderson C, Pastuszak WT, Conway SR, Firshein SI. Arsenic intoxication presenting as a myelodysplastic syndrome: a case report. Am J Hematol. 1991;36(4):291–3.

    Article  PubMed  CAS  Google Scholar 

  178. Kirby MA, Weitzman S, Freedman MH. Juvenile chronic myelogenous leukemia: differentiation from infantile cytomegalovirus infection. Am J Pediatr Hematol Oncol. 1990;12(3):292–6.

    Article  PubMed  CAS  Google Scholar 

  179. Hasle H, Kerndrup G, Jacobsen BB, Heegaard ED, Hornsleth A, Lillevang ST. Chronic parvovirus infection mimicking myelodysplastic syndrome in a child with subclinical immunodeficiency. Am J Pediatr Hematol Oncol. 1994;16(4):329–33.

    PubMed  CAS  Google Scholar 

  180. Bagby GC, Meyers G. Bone marrow failure as a risk factor for clonal evolution: prospects for leukemia prevention. Hematology Am Soc Hematol Educ Program. 2007;2007:40–6.

    Article  Google Scholar 

  181. Wang SA, Pozdnyakova O, Jorgensen JL, Medeiros LJ, Stachurski D, Anderson M, et al. Detection of paroxysmal nocturnal hemoglobinuria clones in patients with myelodysplastic syndromes and related bone marrow diseases, with emphasis on diagnostic pitfalls and caveats. Haematologica. 2009;94(1):29–37.

    Article  PubMed  Google Scholar 

  182. Socie G, Mary JY, de Gramont A, Rio B, Leporrier M, Rose C, et al. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. French Society of Haematology. Lancet. 1996;348(9027):573–7.

    Article  CAS  PubMed  Google Scholar 

  183. Valent P, Bain BJ, Bennett JM, Wimazal F, Sperr WR, Mufti G, et al. Idiopathic cytopenia of undetermined significance (ICUS) and idiopathic dysplasia of uncertain significance (IDUS), and their distinction from low risk MDS. Leuk Res. 2012;36(1):1–5.

    Article  PubMed  Google Scholar 

  184. Valent P, Horny HP, Bennett JM, Fonatsch C, Germing U, Greenberg P, et al. Definitions and standards in the diagnosis and treatment of the myelodysplastic syndromes: Consensus statements and report from a working conference. Leuk Res. 2007;31(6):727–36.

    Article  PubMed  Google Scholar 

  185. Ando K, Tanaka Y, Hashimoto Y, Ohyashiki JH, Sugimori N, Nakao S, et al. PNH-phenotype cells in patients with idiopathic cytopenia of undetermined significance (ICUS) with megakaryocytic hypoplasia and thrombocytopenia. Br J Haematol. 2010;150(6):705–7.

    Article  PubMed  Google Scholar 

  186. Valent P, Jager E, Mitterbauer-Hohendanner G, Mullauer L, Schwarzinger I, Sperr WR, et al. Idiopathic bone marrow dysplasia of unknown significance (IDUS): definition, pathogenesis, follow up, and prognosis. Am J Cancer Res. 2011;1(4):531–41.

    PubMed  Google Scholar 

  187. Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371(26):2488–98.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  188. Welch JS, Ley TJ, Link DC, Miller CA, Larson DE, Koboldt DC, et al. The origin and evolution of mutations in acute myeloid leukemia. Cell. 2012;150(2):264–78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  189. Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014;20(12):1472–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  190. Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371(26):2477–87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  191. Kwok B, Hall JM, Witte JS, Xu Y, Reddy P, Lin K, et al. MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance. Blood. 2015;126(21):2355–61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  192. Malcovati L, Galli A, Travaglino E, Ambaglio I, Rizzo E, Molteni E, et al. Clinical significance of somatic mutation in unexplained blood cytopenia. Blood. 2017;129(25):3371–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  193. Cargo CA, Rowbotham N, Evans PA, Barrans SL, Bowen DT, Crouch S, et al. Targeted sequencing identifies patients with preclinical MDS at high risk of disease progression. Blood. 2015;126(21):2362–5.

    Article  PubMed  CAS  Google Scholar 

  194. Ohgami RS, Ohgami JK, Pereira IT, Gitana G, Zehnder JL, Arber DA. Refining the diagnosis of T-cell large granular lymphocytic leukemia by combining distinct patterns of antigen expression with T-cell clonality studies. Leukemia. 2011;25(9):1439–43.

    Article  CAS  PubMed  Google Scholar 

  195. Huh YO, Medeiros LJ, Ravandi F, Konoplev S, Jorgensen JL, Miranda RN. T-cell large granular lymphocyte leukemia associated with myelodysplastic syndrome: a clinicopathologic study of nine cases. Am J Clin Pathol. 2009;131(3):347–56.

    Article  CAS  PubMed  Google Scholar 

  196. Jerez A, Clemente MJ, Makishima H, Rajala H, Gomez-Segui I, Olson T, et al. STAT3 mutations indicate the presence of subclinical T-cell clones in a subset of aplastic anemia and myelodysplastic syndrome patients. Blood. 2013;122(14):2453–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  197. Marks PW, Mitus AJ. Congenital dyserythropoietic anemias. Am J Hematol. 1996;51(1):55–63.

    Article  PubMed  CAS  Google Scholar 

  198. Hines JD, Cowan DH. Studies on the pathogenesis of alcohol-induced sideroblastic bone-marrow abnormalities. N Engl J Med. 1970;283(9):441–6.

    Article  PubMed  CAS  Google Scholar 

  199. Sharp RA, Lowe JG, Johnston RN. Anti-tuberculous drugs and sideroblastic anaemia. Br J Clin Pract. 1990;44(12):706–7.

    PubMed  CAS  Google Scholar 

  200. Beck EA, Ziegler G, Schmid R, Ludin H. Reversible sideroblastic anemia caused by chloramphenicol. Acta Haematol. 1967;38(1):1–10.

    Article  PubMed  CAS  Google Scholar 

  201. Kandola L, Swannell AJ, Hunter A. Acquired sideroblastic anaemia associated with penicillamine therapy for rheumatoid arthritis. Ann Rheum Dis. 1995;54(6):529–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  202. Ok CY, Medeiros LJ, Hu Y, Bueso-Ramos CE, Wang SA. Transient/reversible ring sideroblasts in bone marrow of patients post cytotoxic therapies for primary malignancies. Leuk Res. 2011;35(12):1605–10.

    Article  PubMed  Google Scholar 

  203. Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7(4):387–97.

    Article  PubMed  CAS  Google Scholar 

  204. Nelson ME, Steensma DP. JAK2 V617F in myeloid disorders: what do we know now, and where are we headed? Leuk Lymphoma. 2006;47(2):177–94.

    Article  PubMed  CAS  Google Scholar 

  205. Ohyashiki K, Aota Y, Akahane D, Gotoh A, Miyazawa K, Kimura Y, et al. The JAK2 V617F tyrosine kinase mutation in myelodysplastic syndromes (MDS) developing myelofibrosis indicates the myeloproliferative nature in a subset of MDS patients. Leukemia. 2005;19(12):2359–60.

    Article  PubMed  CAS  Google Scholar 

  206. Yoshizato T, Dumitriu B, Hosokawa K, Makishima H, Yoshida K, Townsley D, et al. Somatic mutations and clonal hematopoiesis in aplastic anemia. N Engl J Med. 2015;373(1):35–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Wang SA, Galili N, Cerny J, Sechman E, Chen SS, Loew J, et al. Chronic myelomonocytic leukemia evolving from preexisting myelodysplasia shares many features with de novo disease. Am J Clin Pathol. 2006;126(5):789–97.

    Article  PubMed  CAS  Google Scholar 

  208. Head DR. Revised classification of acute myeloid leukemia. Leukemia. 1996;10(11):1826–31.

    PubMed  CAS  Google Scholar 

  209. Liu W, Hasserjian RP, Hu Y, Zhang L, Miranda RN, Medeiros LJ, et al. Pure erythroid leukemia: a reassessment of the entity using the 2008 World Health Organization classification. Mod Pathol. 2010;24(3):375–83.

    Article  PubMed  CAS  Google Scholar 

  210. Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007;110(10):3540–6.

    Article  PubMed  CAS  Google Scholar 

  211. Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354(24):2531–41.

    Article  PubMed  CAS  Google Scholar 

  212. Marti-Carvajal AJ, Anand V, Sola I. Janus kinase-1 and Janus kinase-2 inhibitors for treating myelofibrosis. Cochrane Database Syst Rev. 2015;10(4):CD010298.

    Google Scholar 

  213. Burger JA, Keating MJ, Wierda WG, Hartmann E, Hoellenriegel J, Rosin NY, et al. Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2014;15(10):1090–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  214. O’Brien S, Furman RR, Coutre SE, Sharman JP, Burger JA, Blum KA, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014;15(1):48–58.

    Article  PubMed  CAS  Google Scholar 

  215. Cattaneo C, Spedini P, Casari S, Re A, Tucci A, Borlenghi E, et al. Delayed-onset peripheral blood cytopenia after rituximab: frequency and risk factor assessment in a consecutive series of 77 treatments. Leuk Lymphoma. 2006;47(6):1013–7.

    Article  PubMed  CAS  Google Scholar 

  216. Peyrade F, Bologna S, Delwail V, Emile JF, Pascal L, Ferme C, et al. Combination of ofatumumab and reduced-dose CHOP for diffuse large B-cell lymphomas in patients aged 80 years or older: an open-label, multicentre, single-arm, phase 2 trial from the LYSA group. Lancet Haematol. 2017;4(1):e46–55.

    Article  PubMed  Google Scholar 

  217. Grigg A, Dyer MJ, Diaz MG, Dreyling M, Rule S, Lei G, et al. Safety and efficacy of obinutuzumab with CHOP or bendamustine in previously untreated follicular lymphoma. Haematologica. 2017;102(4):765–72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  218. Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood. 2002;99(10):3554–61.

    Article  PubMed  CAS  Google Scholar 

  219. Scott LJ. Brentuximab vedotin: a review in CD30-positive Hodgkin lymphoma. Drugs. 2017;77(4):435–45.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  220. Brito-Zeron P, Soria N, Munoz S, Bove A, Akasbi M, Belenguer R, et al. Prevalence and clinical relevance of autoimmune neutropenia in patients with primary Sjogren’s syndrome. Semin Arthritis Rheum. 2009;38(5):389–95.

    Article  PubMed  Google Scholar 

  221. Grunebaum E, Cohen A, Roifman CM. Recent advances in understanding and managing adenosine deaminase and purine nucleoside phosphorylase deficiencies. Curr Opin Allergy Clin Immunol. 2013;13(6):630–8.

    Article  PubMed  CAS  Google Scholar 

  222. Cassani B, Mirolo M, Cattaneo F, Benninghoff U, Hershfield M, Carlucci F, et al. Altered intracellular and extracellular signaling leads to impaired T-cell functions in ADA-SCID patients. Blood. 2008;111(8):4209–19.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  223. Lagresle-Peyrou C, Six EM, Picard C, Rieux-Laucat F, Michel V, Ditadi A, et al. Human adenylate kinase 2 deficiency causes a profound hematopoietic defect associated with sensorineural deafness. Nat Genet. 2009;41(1):106–11.

    Article  PubMed  CAS  Google Scholar 

  224. Pannicke U, Honig M, Hess I, Friesen C, Holzmann K, Rump EM, et al. Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2. Nat Genet. 2009;41(1):101–5.

    Article  PubMed  CAS  Google Scholar 

  225. Rochman Y, Spolski R, Leonard WJ. New insights into the regulation of T cells by gamma(c) family cytokines. Nat Rev Immunol. 2009;9(7):480–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  226. Macchi P, Villa A, Giliani S, Sacco MG, Frattini A, Porta F, et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature. 1995;377(6544):65–8.

    Article  PubMed  CAS  Google Scholar 

  227. Resnick ES, Moshier EL, Godbold JH, Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood. 2012;119(7):1650–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  228. Salzer U, Warnatz K, Peter HH. Common variable immunodeficiency: an update. Arthritis Res Ther. 2012;14(5):223.

    Article  PubMed  PubMed Central  Google Scholar 

  229. Chen K, Coonrod EM, Kumanovics A, Franks ZF, Durtschi JD, Margraf RL, et al. Germline mutations in NFKB2 implicate the noncanonical NF-kappaB pathway in the pathogenesis of common variable immunodeficiency. Am J Hum Genet. 2013;93(5):812–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  230. Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, et al. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110delta result in T cell senescence and human immunodeficiency. Nat Immunol. 2014;15(1):88–97.

    Article  PubMed  CAS  Google Scholar 

  231. Angulo I, Vadas O, Garcon F, Banham-Hall E, Plagnol V, Leahy TR, et al. Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage. Science. 2013;342(6160):866–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  232. Nowak-Wegrzyn A, Crawford TO, Winkelstein JA, Carson KA, Lederman HM. Immunodeficiency and infections in ataxia-telangiectasia. J Pediatr. 2004;144(4):505–11.

    Article  PubMed  Google Scholar 

  233. Ancliff PJ, Blundell MP, Cory GO, Calle Y, Worth A, Kempski H, et al. Two novel activating mutations in the Wiskott-Aldrich syndrome protein result in congenital neutropenia. Blood. 2006;108(7):2182–9.

    Article  PubMed  CAS  Google Scholar 

  234. Kainulainen L, Lassila O, Ruuskanen O. Cartilage-hair hypoplasia: follow-up of immunodeficiency in two patients. J Clin Immunol. 2014;34(2):256–9.

    Article  PubMed  Google Scholar 

  235. Etzioni A, Benderly A, Rosenthal E, Shehadah V, Auslander L, Lahat N, et al. Defective humoral and cellular immune functions associated with veno-occlusive disease of the liver. J Pediatr. 1987;110(4):549–54.

    Article  PubMed  CAS  Google Scholar 

  236. Grever MR, Abdel-Wahab O, Andritsos LA, Banerji V, Barrientos J, Blachly JS, et al. Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia. Blood. 2017;129(5):553–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  237. Tiacci E, Trifonov V, Schiavoni G, Holmes A, Kern W, Martelli MP, et al. BRAF mutations in hairy-cell leukemia. N Engl J Med. 2011;364(24):2305–15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  238. Hsu AP, Johnson KD, Falcone EL, Sanalkumar R, Sanchez L, Hickstein DD, et al. GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome. Blood. 2013;121(19):3830–7. S1–7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  239. Dickinson RE, Griffin H, Bigley V, Reynard LN, Hussain R, Haniffa M, et al. Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency. Blood. 2011;118(10):2656–8.

    Article  PubMed  CAS  Google Scholar 

  240. Hsu AP, Sampaio EP, Khan J, Calvo KR, Lemieux JE, Patel SY, et al. Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood. 2011;118(10):2653–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  241. Vinh DC, Patel SY, Uzel G, Anderson VL, Freeman AF, Olivier KN, et al. Autosomal dominant and sporadic monocytopenia with susceptibility to mycobacteria, fungi, papillomaviruses, and myelodysplasia. Blood. 2010;115(8):1519–29.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  242. Porwit A, van de Loosdrecht AA, Bettelheim P, Brodersen LE, Burbury K, Cremers E, et al. Revisiting guidelines for integration of flow cytometry results in the WHO classification of myelodysplastic syndromes-proposal from the International/European LeukemiaNet Working Group for Flow Cytometry in MDS. Leukemia. 2014;28(9):1793–8.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Sanam Loghavi M.D.

  2. Department of Pathology, WRN244, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA

    Robert P. Hasserjian M.D.

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  1. Sanam Loghavi M.D.
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Correspondence to Robert P. Hasserjian M.D. .

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  1. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Sa A. Wang

  2. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA

    Robert P. Hasserjian

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Loghavi, S., Hasserjian, R.P. (2018). Cytopenias: Reactive and Neoplastic. In: Wang, S., Hasserjian, R. (eds) Diagnosis of Blood and Bone Marrow Disorders. Springer, Cham. https://doi.org/10.1007/978-3-319-20279-2_2

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