Most adult patients with hematopoietic failure due to myelodysplastic syndrome (MDS) are treated with supportive care measures, including hematopoietic growth factors (epoetin alfa, darbepoetin alfa, filgrastim, pegfilgrastim, sargramostim), red blood cell or platelet transfusions, and antimicrobial agents. Allogeneic stem cell transplantation can be curative, but only a small subset of patients are eligible for transplantation, and until recently there were few options other than supportive care for transplant-ineligible patients. Since 2004, the US Food and Drug Administration (FDA) has approved three new therapies specifically for the indication of MDS: two DNA methyltransferase inhibitors (azacitidine and decitabine) and an immunomodulatory agent (lenalidomide). Several other drugs are used by clinicians for treatment of patients with MDS, but are not specifically FDA-approved for this indication. With several therapeutic options available, yet none of them effective in the majority of cases, it can be challenging for clinicians to choose the most appropriate treatment for an individual patient. Here we discuss a risk-based management approach to MDS that incorporates recent data regarding these new therapies. While many questions remain about the optimal use of newer agents, the long-standing perception of MDS as a syndrome where therapeutic nihilism is the only realistic approach is slowly beginning to change.
For many years, there were few attractive treatment options for patients diagnosed with a form of myelodysplastic syndrome (MDS) beyond supportive and palliative care or, for a small number of younger patients with good performance status and a suitable human leukocyte antigen (HLA)-matched donor, allogeneic hematopoietic stem cell transplantation.[1-4] Chemotherapy regimens similar to those administered to patients with acute myeloid leukemia (AML) are generally too toxic for routine use in the typical older patient with MDS (median age at diagnosis: ~65 years), and many patients never recover hematopoiesis after such aggressive cytoreductive therapy. Furthermore, MDS patients who achieve a complete hematologic remission after antileukemic chemotherapy usually relapse within a few months. A number of pilot studies were conducted in the 1980s and 1990s to try to improve this grim situation (eg, with retinoic acid, amifostine [Ethyol]), but most such clinical trials showed little benefit.
In the past 3 years, the US Food and Drug Administration (FDA) has approved three disease-modifying therapies specifically for use in patients with MDS.[5,6] Additionally, several investigators have described their experiences in the MDS setting with drugs approved for other indications. While it is questionable whether a substantial improvement in the natural history of the disease has truly been achieved, it is clear that some patients benefit from these therapies.[5,7] The expanding repertoire of available treatments for MDS means that choosing the right therapy for a newly diagnosed patient is becoming increasingly challenging. Here, we discuss the agents most commonly used for MDS therapy at present, and outline a strategy for management based on an assessment of an individual patient's risk for cytopenia-related complications, disease progression, and death. For patients who are disinclined to pursue newer therapies or cannot afford them, good palliative and supportive care is still a reasonable option.
Accurate Assessment of Risk
The conditions grouped together as MDS are as diverse as the patients suffering from them. Some patients with this diagnosis progress rapidly to AML or die from cytopenia-related complications within just a few months of diagnosis, while others do well for many years with a simple strategy of observation and "watchful waiting." In view of this heterogeneity, predicting the risk the disease confers to an individual patient is critically important, especially since all of the therapies currently used for MDS carry the potential for serious adverse effects. Given that the only curative therapy for MDS remains stem cell transplantation, it is important to ensure that the adverse effects of any other proposed treatment—where the goal is not cure—are unlikely to be greater than the morbidity of the disease itself. Unfortunately, the current prognostic methods for MDS are rather blunt tools, and accurate risk assessment remains a long way off.
Most clinicians have become comfortable using the simple 1997 International Prognostic Scoring System (IPSS) for assessment of the likelihood of AML transformation or death in de novo MDS (Table 1). The IPSS takes three key factors into account—the proportion of undifferentiated blasts in the patient's blood and marrow (as measured by the manual aspirate differential, not by flow cytometry, which tends to overestimate blast numbers), the cytogenetic risk profile, and the number of cytopenias that the patient has—in order to come up with a four-category prognostic assessment. However, while the IPSS was an important step forward, it is not perfect: As illustrated in Figure 1, any given IPSS category is associated with a broad range of clinical outcomes.
The 2001 MDS classification system of the World Health Organization (WHO) divides MDS into eight categories (Table 3). Although intended as a clinicopathologic classification system rather than a rigorous prognostic tool, the WHO schema does help clinicians perform risk assessment. For instance, forms of MDS that are limited to erythroid dysplasia are now recognized as carrying a better prognosis than forms where marrow dysplasia involves multiple cell lineages; also, patients with excess blasts (> 5%, and especially > 10%) in their bone marrow have a worse outlook than those with a normal blast count. The best outcomes are for patients with classic 5q- syndrome, who enjoy a median survival on the order of 8 to 10 years. A recent proposal to integrate the IPSS with the WHO classification into a "World Health Organization Prognostic Scoring System (WPSS)" (Table 4 and Figure 2) is currently being independently evaluated.
It is important to note that the IPSS is based on 816 patients with de novo MDS. Patients with known secondary MDS (ie, prior exposure to chemotherapy with alkylating agents or topoisomerase inhibitors, therapeutic or accidental exposure to ionizing radiation, or both) have a very high risk of AML progression and should probably be considered similarly to the highest IPSS risk group. Additionally, there are many cytogenetic and molecular genetic risk categories that are not accounted for by the IPSS, because many of the less common MDS-associated karyotypes were represented by only a few patients in the 1997 analysis, resulting in inadequate statistical power to detect the difference between these small groups in outcome.[16-18] However, small cohort studies have suggested that some patients with certain uncommon but recurrent karyotypic changes (eg, abnormalities of chromosome 17p that involve the TP53 gene) do particularly poorly.[16,19,20] These factors need to be considered when deciding on a particular therapeutic course for an individual patient.
The authors have no personal financial conflicts of interest to report. Dr. Steensma has been an investigator on clinical research supported by Amgen, Ortho Biotech, MGI Pharma, Novartis Oncology, and GlaxoSmithKline, for which all support was given to Mayo Clinic, not the individual investigator. Dr. Tefferi has been an investigator for similar clinical trials involving Celgene and Millenium Pharmaceuticals. Dr. Steensma is supported by Paul Calabresi award K12 CA90628 from the National Cancer Institute, and Dr. Tefferi by a grant from the Myeloproliferative Disorders Foundation.
1. Hofmann WK, Koeffler HP: Myelodysplastic syndrome. Annu Rev Med 56:1-16, 2005.
2. National Comprehensive Cancer Network: NCCN practice guidelines for the myelodysplastic syndromes (version 1). Oncology (Williston Park) 12(11A):53-80, 1998.
3. Steensma DP, Bennett JM: The myelodysplastic syndromes: diagnosis and treatment. Mayo Clin Proc 81:104-130, 2006.
4. Bowen D, Culligan D, Jowitt S, et al: Guidelines for the diagnosis and therapy of adult myelodysplastic syndromes. Br J Haematol 120:187-200, 2003.
5. List AF: New agents in the treatment of MDS. Clin Adv Hematol Oncol 3:832-834, 2005.
6. Nivatpumin PJ, Gore SD: Emerging drugs for the treatment of myelodysplastic syndrome. Expert Opin Emerg Drugs 10:569-590, 2005.
7. Tefferi A, Letendre L: Drug therapy for myelodysplastic syndrome: Building evidence for action. Cancer 106:1650-1652, 2006.
8. Steensma DP, List AF: Genetic testing in the myelodysplastic syndromes: Molecular insights into hematologic diversity. Mayo Clin Proc 80:681-698, 2005.
9. Mufti GJ: Pathobiology, classification, and diagnosis of myelodysplastic syndrome. Best Pract Res Clin Haematol 17:543-557, 2004.
10. Greenberg P, Cox C, LeBeau MM, et al: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079-2088, 1997.
11. Jaffe ES, Harris NL, Stein H, et al (eds): WHO Classification: Tumours Of Haematopoietic And Lymphoid Tissues. Lyon; International Agency For Research on Cancer (IARC) Press; 2001.
12. Malcovati L, Porta MG, Pascutto C, et al: Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making. J Clin Oncol 23:7594-7603, 2005.
13. Giagounidis AA, Germing U, Wainscoat JS, et al: The 5q- syndrome. Hematology 9:271-277, 2004.
14. Malcovati L, Germing U, Kuendgen A, et al: A WHO classification-based prognostic scoring system (WPSS) for predicting survival in myelodysplastic syndromes (abstract 788). Blood 106:A788, 2005.
15. Smith MA, McCaffrey RP, Karp JE: The secondary leukemias: Challenges and research directions. J Natl Cancer Inst 88:407-418, 1996.
16. Sole F, Luno E, Sanzo C, et al: Identification of novel cytogenetic markers with prognostic significance in a series of 968 patients with primary myelodysplastic syndromes. Haematologica 90:1168-1178, 2005.
17. Olney HJ, Le Beau MM: The cytogenetics of myelodysplastic syndromes. Best Pract Res Clin Haematol 14:479-495, 2001.
18. Block AW, Carroll AJ, Hagemeijer A, et al: Rare recurring balanced chromosome abnormalities in therapy-related myelodysplastic syndromes and acute leukemia: Report from an international workshop. Genes Chromoisomes Cancer 33:401-412, 2002.
19. Kita-Sasai Y, Horiike S, Misawa S, et al: International prognostic scoring system and TP53 mutations are independent prognostic indicators for patients with myelodysplastic syndrome. Br J Haematol 115:309-312, 2001.
20. Horiike S, Kita-Sasai Y, Nakao M, et al: Configuration of the TP53 gene as an independent prognostic parameter of myelodysplastic syndrome. Leuk Lymphoma 44:915-922, 2003.
21. Benesch M, Deeg HJ: Hemopoietic cell transplantation for myelodysplastic syndromes. Curr Hematol Rep 2:209-216, 2003.
22. Wallen H, Gooley TA, Deeg HJ, et al: Ablative allogeneic hematopoietic cell transplantation in adults 60 years of age and older. J Clin Oncol 23:3439-3446, 2005.
23. Deeg HJ, Shulman HM, Anderson JE, et al: Allogeneic and syngeneic marrow transplantation for myelodysplastic syndrome in patients 55 to 66 years of age. Blood 95:1188-1194, 2000.
24. Deeg HJ: Optimization of transplant regimens for patients with myelodysplastic syndrome (MDS). Hematology (Am Soc Hematol Educ Program) pp 167-73, 2005.
25. Cutler CS, Lee SJ, Greenberg P, et al: A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: Delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood 104:579-585, 2004.
26. Kaminskas E, Farrell A, Abraham S, et al: Approval summary: Azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res 11:3604-3608, 2005.
27. Silverman LR: DNA methyltransferase inhibitors in myelodysplastic syndrome. Best Pract Res Clin Haematol 17:585-594, 2004.
28. Jones PA, Baylin SB: The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415-428, 2002.
29. Jaenisch R, Bird A: Epigenetic regulation of gene expression: How the genome integrates intrinsic and environmental signals. Nat Genet 33(suppl):245-254, 2003.
30. Daskalakis M, Nguyen TT, Nguyen C, et al: Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2'-deoxycytidine (decitabine) treatment. Blood 100:2957-2964, 2002.
31. Silverman LR, Demakos EP, Peterson BL, et al: Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: A study of the cancer and leukemia group B. J Clin Oncol 20:2429-2440, 2002.
32. Kornblith AB, Herndon JE 2nd, Silverman LR, et al: Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: A Cancer and Leukemia Group B study. J Clin Oncol 20:2441-2452, 2002.
33. Silverman LR, McKenzie DR, Peterson BL, et al: Response rates using International Working Group (IWG) criteria in patients with myelodysplastic syndromes (MDS) treated with azacitidine (abstract 2526). Blood 106:A2526, 2005.
34. Gore SD: Six (or more) drugs in search of a mechanism: DNA methyltransferase and histone deacetylase inhibitors in the treatment of myelodysplastic syndromes. J Natl Compr Canc Netw 4:83-90, 2006.
35. McKeage K, Croom KF: Decitabine: In myelodysplastic syndromes. Drugs 66:951-958, 2006.
36. de Vos D, van Overveld W: Decitabine: A historical review of the development of an epigenetic drug. Ann Hematol 84(suppl 13):3-8, 2005.
37. Peters GJ, Ackland SP: New antimetabolites in preclinical and clinical development. Exp Opin Invest Drugs 5:637-679, 1996.
38. Li LH, Olin EJ, Buskirk HH, et al: Cytotoxicity and mode of action of 5-azacytidine on L1210 leukemia. Cancer Res 30:2760-2769, 1970.
39. Momparler RL, Momparler LF, Samson J: Comparison of the antileukemic activity of 5-AZA-2'-deoxycytidine, 1-beta-D-arabinofuranosylcytosine and 5-azacytidine against L1210 leukemia. Leuk Res 8:1043-1049, 1984.
40. Kantarjian H, Issa JP, Rosenfeld CS, et al: Decitabine improves patient outcomes in myelodysplastic syndromes: Results of a phase III randomized study. Cancer 106:1794-1803, 2006.
41. Kantarjian H, Oki Y, Garcia-Manero G, et al: Results of a randomized study of three schedules of low-dose decitabine in higher risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood August 1, 2006 [Epub ahead of print].
42. Lyons R, Cosgriff T, Modi S, et al: Azacitidine (Vidaza®) treatment response assessed using three alternative dosing schedules in patients with myelodysplastic syndromes (MDS) (abstract 2517). Blood 106:A2517, 2005.
43. van den Bosch J, Lubbert M, Verhoef G, et al: The effects of 5-aza-2'-deoxycytidine (decitabine) on the platelet count in patients with intermediate and high-risk myelodysplastic syndromes. Leuk Res 28:785-790, 2004.
44. Wijermans PW, Lubbert M, Verhoef G, et al: An epigenetic approach to the treatment of advanced MDS: The experience with the DNA demethylating agent 5-aza-2'-deoxycytidine (decitabine) in 177 patients. Ann Hematol 84(suppl 13):9-17, 2005.
45. Silverman LR, McKenzie DR, Peterson BL, et al: Analysis of survival, AML transformation, and transfusion independence in patients with high-risk myelodysplastic syndromes (MDS) receiving azacitidine determined using a prognostic model (abstract 2523). Blood 106:A2523, 2005.
46. Fukumoto JS, Greenberg PL: Management of patients with higher risk myelodysplastic syndromes. Crit Rev Oncol Hematol 56:179-192, 2005.
47. Lubbert M, Minden M: Decitabine in acute myeloid leukemia. Semin Hematol 42(2 suppl 2):S38-S42, 2005.
48. Sudan N, Rossetti JM, Shadduck RK, et al: Treatment of acute myelogenous leukemia with outpatient azacitidine. Cancer 107:1839-1843, 2006.
49. Musto P: Thalidomide therapy for myelodysplastic syndromes: current status and future perspectives. Leuk Res 28:325-332, 2004.
50. Raza A, Meyer P, Dutt D, et al: Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes. Blood 98:958-965, 2001.
51. Moreno-Aspitia A, Geyer S, Li C, et al: N998B: Multicenter phase II trial of thalidomide (Thal) in adult patients with myelodysplastic syndromes (MDS) (abstract 354). Blood 100:96a, 2002.
52. Zorat F, Shetty V, Dutt D, et al: The clinical and biological effects of thalidomide in patients with myelodysplastic syndromes. Br J Haematol 115:881-894, 2001.
53. Sekeres MA, List A: Lenalidomide (Revlimid, CC-5013) in myelodysplastic syndromes: is it any good? Curr Hematol Rep 4:182-185, 2005.
54. List A, Kurtin S, Roe DJ, et al: Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 352:549-557, 2005.
55. List A, Dewald G, Bennett J, et al: Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 355:1456-1465, 2006.
56. List AF, Dewald G, Bennett J, et al: Results of the MDS-002 and -003 international phase II studies evaluating lenalidomide (CC-5013, Revlimid) in the treatment of transfusion-dependent (TD) patients with myelodysplastic syndrome (MDS) (abstract 0772). 10th Congress of the European Hematology Association. Int J Hematol 2005.
57. Mesa RA, Tefferi A, Li CY, et al: Hematologic and cytogenetic response to lenalidomide monotherapy in acute myeloid leukemia arising from JAK2(V617F) positive, del(5)(q13q33) myelodysplastic syndrome. Leukemia 20:2063-2064, 2006.
58. Aivado M, Rong A, Stadler M, et al: Favourable response to antithymocyte or antilymphocyte globulin in low-risk myelodysplastic syndrome patients with a 'non-clonal' pattern of X-chromosome inactivation in bone marrow cells. Eur J Haematol 68:210-216, 2002.
59. Yazji S, Giles FJ, Tsimberidou AM, et al: Antithymocyte globulin (ATG)-based therapy in patients with myelodysplastic syndromes. Leukemia 17:2101-2106, 2003.
60. Molldrem JJ, Leifer E, Bahceci E, et al: Antithymocyte globulin for treatment of the bone marrow failure associated with myelodysplastic syndromes. Ann Intern Med 137:156-163, 2002.
61. Lim ZY, Killick S, Cavenagh J, et al: European multi-centre study on the use of anti-thymocyte globulin in the treatment of myelodysplastic syndromes (abstract 2518). Blood 106:A2518, 2005.
62. Stadler M, Germing U, Kliche KO, et al: A prospective, randomised, phase II study of horse antithymocyte globulin vs rabbit antithymocyte globulin as immune-modulating therapy in patients with low-risk myelodysplastic syndromes. Leukemia 18:460-465, 2004.
63. Saunthararajah Y, Nakamura R, Wesley R, et al: A simple method to predict response to immunosuppressive therapy in patients with myelodysplastic syndrome. Blood 102:3025-3027, 2003.
64. Shimamoto T, Tohyama K, Okamoto T, et al: Cyclosporin A therapy for patients with myelodysplastic syndrome: Multicenter pilot studies in Japan. Leuk Res 27:783-788, 2003.
65. Stasi R, Amadori S: Infliximab chimaeric anti-tumour necrosis factor alpha monoclonal antibody treatment for patients with myelodysplastic syndromes. Br J Haematol 116:334-337, 2002.
66. Raza A, Candoni A, Khan U, et al: Remicade as TNF suppressor in patients with myelodysplastic syndromes. Leuk Lymphoma 45:2099-2104, 2004.
67. Deeg HJ, Gotlib J, Beckham C, et al: Soluble TNF receptor fusion protein (etanercept) for the treatment of myelodysplastic syndrome: A pilot study. Leukemia 16:162-164, 2002.
68. Barrett J, Saunthararajah Y, Molldrem J: Myelodysplastic syndrome and aplastic anemia: Distinct entities or diseases linked by a common pathophysiology? Semin Hematol 37:15-29, 2000.
69. Biesma DH, van den Tweel JG, Verdonck LF: Immunosuppressive therapy for hypoplastic myelodysplastic syndrome. Cancer 79:1548-1551, 1997.
70. Herman JG, Baylin SB: Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349:2042-2054, 2003.
71. Bhalla K, List A: Histone deacetylase inhibitors in myelodysplastic syndrome. Best Pract Res Clin Haematol 17:595-611, 2004.
72. Kuendgen A, Knipp S, Fox F, et al: Results of a phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia. Ann Hematol 84(suppl 13):61-66, 2005.
73. Pilatrino C, Cilloni D, Messa E, et al: Increase in platelet count in older, poor-risk patients with acute myeloid leukemia or myelodysplastic syndrome treated with valproic acid and all-trans retinoic acid. Cancer 104:101-109, 2005.
74. Schiller GJ, Slack J, Hainsworth JD, et al: Phase II multicenter study of arsenic trioxide in patients with myelodysplastic syndromes. J Clin Oncol 24:2456-2464, 2006.
75. Vey N, Bosly A, Guerci A, et al: Arsenic trioxide in patients with myelodysplastic syndromes: A phase II multicenter study. J Clin Oncol 24:2465-2471, 2006.
76. Stone RM: Is intravenous arsenic trioxide a useful therapy in myelodysplastic syndromes? J Clin Oncol 24:2414-2416, 2006.
77. Hellstrom-Lindberg E: Update on supportive care and new therapies: Immunomodulatory drugs, growth factors and epigenetic-acting agents. Hematology (Am Soc Hematol Educ Program) pp 161-166, 2005.
78. Casadevall N, Durieux P, Dubois S, et al: Health, economic, and quality-of-life effects of erythropoietin and granulocyte colony-stimulating factor for the treatment of myelodysplastic syndromes: A randomized, controlled trial. Blood 104:321-327, 2004.
79. Stein RS, Abels RI, Krantz SB: Pharmacologic doses of recombinant human erythropoietin in the treatment of myelodysplastic syndromes. Blood 78:1658-1663, 1991.
80. Hellstrom-Lindberg E, Gulbrandsen N, Lindberg G, et al: A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: Significant effects on quality of life. Br J Haematol 120:1037-1046, 2003.
81. Goy A, Belanger C, Casadevall N, et al: High doses of intravenous recombinant erythropoietin for the treatment of anaemia in myelodysplastic syndrome. Br J Haematol 84:232-237, 1993.
82. Mannone L, Gardin C, Quarre MC, et al: High-dose darbepoetin alpha in the treatment of anaemia of lower risk myelodysplastic syndrome results of a phase II study. Br J Haematol 133:513-519, 2006.
83. Stasi R, Abruzzese E, Lanzetta G, et al: Darbepoetin alfa for the treatment of anemic patients with low- and intermediate-1-risk myelodysplastic syndromes. Ann Oncol 16:1921-1927, 2005.
84. Musto P, Lanza F, Balleari E, et al: Darbepoetin alpha for the treatment of anaemia in low-intermediate risk myelodysplastic syndromes. Br J Haematol 128:204-209, 2005.
85. Greenberg PL, NCCN Panel: National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology-v.1.2005: Myelodysplastic syndromes (Sept 2004). Vol 2005, Chicago, 2005.
86. Clavio M, Balleari E, Garrone A, et al: Haemopoietic growth factors in myelodysplastic syndromes: Towards patient-oriented therapy? J Exp Clin Cancer Res 24:5-16, 2005.
87. Balleari E, Rossi E, Clavio M, et al: Erythropoietin plus granulocyte colony-stimulating factor is better than erythropoietin alone to treat anemia in low-risk myelodysplastic syndromes: Results from a randomized single-centre study. Ann Hematol 85:174-180, 2006.
88. Arshad M, Seiter K, Bilaniuk J, et al: Side effects related to cancer treatment: CASE 2. Splenic rupture following pegfilgrastim. J Clin Oncol 23:8533-8534, 2005.
89. Tsimberidou AM, Giles FJ, Khouri I, et al: Low-dose interleukin-11 in patients with bone marrow failure: Update of the M. D. Anderson Cancer Center experience. Ann Oncol 16:139-145, 2005.
90. Kaushansky K: Lineage-specific hematopoietic growth factors. N Engl J Med 354:2034-2045, 2006.
91. Tefferi A: Iron chelation therapy for myelodysplastic syndrome: If and when. Mayo Clin Proc 81:197-198, 2006.
92. Greenberg PL: Myelodysplastic syndromes: Iron overload consequences and current chelating therapies. J Natl Compr Canc Netw 4:91-96, 2006.
93. Cazzola M, Malcovati L: Myelodysplastic syndromes-coping with ineffective hematopoiesis. N Engl J Med 352:536-538, 2005.
94. Cappellini MD: Iron-chelating therapy with the new oral agent ICL670 (Exjade). Best Pract Res Clin Haematol 18:289-298, 2005.
95. Bjorkman SE: Chronic refractory anemia with sideroblastic bone marrow: A study of four cases. Blood 11:250-259, 1956.
96. Bennett JM, Catovsky D, Daniel MT, et al: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51:189-199, 1982.
97. Gattermann N, Aul C, Schneider W: Two types of acquired idiopathic sideroblastic anaemia (AISA). Br J Haematol 74:45-52, 1990.
98. Garand R, Gardais J, Bizet M, et al: Heterogeneity of acquired idiopathic sideroblastic anaemia (AISA). Leuk Res 16:463-468, 1992.
99. Germing U, Gattermann N, Aivado M, et al: Two types of acquired idiopathic sideroblastic anaemia (AISA): A time-tested distinction. Br J Haematol 108:724-728,
100. Cotter PD, May A, Fitzsimons EJ, et al: Late-onset X-linked sideroblastic anemia. Missense mutations in the erythroid delta-aminolevulinate synthase (ALAS2) gene in two pyridoxine-responsive patients initially diagnosed with acquired refractory anemia and ringed sideroblasts.[see comment]. J Clin Invest 96:2090-2096, 1995.
101. Alcindor T, Bridges KR: Sideroblastic anaemias. Br J Haematol 116:733-743, 2002.
102. Germing U, Gattermann N, Minning H, et al: Problems in the classification of CMML-dysplastic versus proliferative type. Leuk Res 22:871-878, 1998.
103. Gonzalez-Medina I, Bueno J, Torrequebrada A, et al: Two groups of chronic myelomonocytic leukaemia: Myelodysplastic and myeloproliferative. Prognostic implications in a series of a single center. Leuk Res 26:821-824, 2002.
104. Magnusson MK, Meade KE, Nakamura R, et al: Activity of STI571 in chronic myelomonocytic leukemia with a platelet-derived growth factor beta receptor fusion oncogene. Blood 100:1088-1091, 2002.
105. Wattel E, Guerci A, Hecquet B, et al: A randomized trial of hydroxyurea versus VP16 in adult chronic myelomonocytic leukemia. Groupe Francais des Myelodysplasies and European CMML Group. Blood 88:2480-2487, 1996.
106. Dhruva A, Damon LE, Linker C, et al: A retrospective review of outcomes of patients with chronic myelomoncytic leukemia treated with 5-azacitidine (abstract 4931). Blood 106:A4931, 2005.
107. Harris NL, Jaffe ES, Diebold J, et al: World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: Report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol 17:3835-3849, 1999.
108. Komrokji R, Bennett JM: The myelodysplastic syndromes: Classification and prognosis. Curr Hematol Rep 2:179-185, 2003.