Myelodysplastic syndrome medical therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Nawal Muazam M.D.[2]
Overview
Medical therapy
The goals of therapy are to control symptoms, improve quality of life, improve overall survival, and decrease progression to acute myelogenous leukemia.
The IPSS scoring system can help triage patients for more aggressive treatment (i.e. bone marrow transplant) as well as help determine the best timing of this therapy.[1] [2] Supportive care with blood product support and hematopoeitic growth factors (e.g. erythropoietin) is the mainstay of therapy. The regulatory environment for the use of erythropoietins is evolving, according to a recent US Medicare National Coverage Determination. No comment on the use of hematopoeitic growth factors for MDS was made in that document.[3]
The IPSS uses 3 criteria; cytogenetic abnormalities, proportion of bone marrow myeloblasts and number of cytopenias. Points are assigned to these variables and are added to create 4 risk groups; low, intermediate 1, intermediate 2 and high risk. If patients have >10% blasts in their bone marrow by morphology they are automatically classified as having higher risk MDS. Patients with chromosome 7 abnormalities, loss of chromosome 7 or complex cytogenetics typically have high-risk MDS. A major limitation of the IPSS is that it does not distinguish between patients with severe and modest degrees of cytopenias; this may influence outcome.
Survival and AML evolution score
| Prognostic Variable | 0 | 0.5 | 1 | 1.5 | 2 |
|---|---|---|---|---|---|
| Bone marrow blasts (%) | <5 | 5-10 | X | 11-20 | 21-30 |
| Karyotype * | good | intermediate | poor | X | X |
| Cytopenias ** | 0 or 1 | 2 or 3 | X | X | X |
- Good = normal or any 1 of the following; deletion Y, deletion 5q, deletion 20q.
Intermediate = other abnormalities. Poor = complex (>/= 3 abnormalities) or chromosome 7 abnormalities.
- Hemoglobin < 10 g/dl, ANC<1800 /uL, Platelets <100,000.
| IPSS Risk Category | Low | Intermediate 1 | Intermediate 2 | High |
|---|---|---|---|---|
| Combined score | 0 | 0.5-1 | 1.5-2 | >/=2.5 |
| AML evolution | 19% | 30% | 33% | 45% |
| Median time to AML (years) | 9.4 | 3.3 | 1.1 | 0.2 |
| Median survival (years) | 5.7 | 3.5 | 1.2 | 0.4 |
Lower risk disease includes those classified as low or intermediate 1 with a combined IPSS score of 1 or lower. For these patients observation and supportive care only has been advocated. (However, once blood transfusions are required then some form of treatment should be considered.)
Since 2004 3 medications have been approved for MDS; 5-azacytidine and decitabine are hypomethylating agents, lenalidomide is immunomodulatory. Lenalidomide is especially useful in the treatment of 5q minus syndrome; for these patients the medication not only improves counts but it also has a high complete response rate in the bone marrow and a high remission rate for the chromosome. For non-5q deletion, low-risk MDS patients treatment options include lenalidomide and demethylating agents.
DNA-methyltransferase inhibitors; normally methylation of cytosine in gene promoters causes them to become silent; they would otherwise cause terminal differentiation. There is survival benefit with the hypomethylating agents (Decitabine & Azacitadine)in higher-risk disease (intermediate-2 or high risk disease).Azacitidine and Decitabine are different chemically and patients whose disease doesn't respond or becomes refractory to one may respond to the other. The recommendation is to proceed until progression; sometimes stopping allows the disease to relapse or it relapses as it is resistant disease. The major toxicities are nausea, vomiting, diarrhea, cytopenias and fatigue. [4][5][6][7] [8][9][10][11]
IMiDS, such as Lenalidomide are for erythroid failure such as in transfusion-dependent del(5q). The response rate (~67%)is independent of the karyoptype. Treatment can give a positive cytopgenetic response, the patient becomes transfusion-free and would no longer require Erythropoietin. With treatment there is a transient decrease in the leukocytes and platelets. It has been known to be useful in paients without the 5q deletion with ~25% of patients experiencing a significant response in hemoglobin levels. [12] [13].
Contraindicated medications
High-risk myelodysplastic syndromes is considered an absolute contraindication to the use of the following medications:
References
- ↑ Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyshiki K, Toyama K, Aul C, Hufti G, Bennett J. 89 (6). PMID 9058730. Missing or empty
|title=(help) - ↑ Cutler CS, Lee SJ, Greenberg P, Deeg HJ, Perez WS, Anasetti C, Bolwell BJ, Cairo MS, Gale RP, Klein JP, Lazarus HM, Liesveld JL, McCarthy PL, Milone GA, Rizzo JD, Schultz KR, Trigg ME, Keating A, Weisdorf DJ, Antin JH, Horowitz MM (2004). "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 (2): 579–85. PMID 15039286.
- ↑ "Centers for Medicare & Medicaid Services". Retrieved 2007-10-29.
- ↑ Wijermans P, Lübbert M, Verhoef G; et al. (2000). "Low-dose 5-aza-2'-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients". J. Clin. Oncol. 18 (5): 956–62. PMID 10694544.
- ↑ Lübbert M, Wijermans P, Kunzmann R; et al. (2001). "Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine". Br. J. Haematol. 114 (2): 349–57. PMID 11529854.
- ↑ Silverman LR, Demakos EP, Peterson BL; et al. (2002). "Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B". J. Clin. Oncol. 20 (10): 2429–40. PMID 12011120.
- ↑ Silverman LR, McKenzie DR, Peterson BL; et al. (2006). "Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B". J. Clin. Oncol. 24 (24): 3895–903. doi:10.1200/JCO.2005.05.4346. PMID 16921040.
- ↑ Kantarjian HM, O'Brien S, Shan J; et al. (2007). "Update of the decitabine experience in higher risk myelodysplastic syndrome and analysis of prognostic factors associated with outcome". Cancer. 109 (2): 265–73. doi:10.1002/cncr.22376. PMID 17133405.
- ↑ Kantarjian H, Issa JP, Rosenfeld CS; et al. (2006). "Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study". Cancer. 106 (8): 1794–803. doi:10.1002/cncr.21792. PMID 16532500.
- ↑ Kantarjian H, Oki Y, Garcia-Manero G; et al. (2007). "Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia". Blood. 109 (1): 52–7. doi:10.1182/blood-2006-05-021162. PMID 16882708.
- ↑ Blum W, Klisovic RB, Hackanson B; et al. (2007). "Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia". J. Clin. Oncol. 25 (25): 3884–91. doi:10.1200/JCO.2006.09.4169. PMID 17679729.
- ↑ List A, Dewald G, Bennett J; et al. (2006). "Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion". N. Engl. J. Med. 355 (14): 1456–65. doi:10.1056/NEJMoa061292. PMID 17021321.
- ↑ "Lenalidomide (Revlimid) for anemia of myelodysplastic syndrome". The Medical letter on drugs and therapeutics. 48 (1232): 31–2. 2006. PMID 16625140.