Treatment of high or very high risk myelodysplastic syndromes
- Elihu H Estey, MD
Elihu H Estey, MD
- University of Washington School of Medicine
- Stanley L Schrier, MD
Stanley L Schrier, MD
- Editor-in-Chief — Hematology
- Section Editor — Myeloproliferative Disorders; Red Blood Cell Disorders
- Professor of Medicine
- Stanford University School of Medicine
The myelodysplastic syndromes (MDS) encompass a series of hematologic conditions characterized by chronic cytopenias (anemia, neutropenia, thrombocytopenia) accompanied by abnormal cellular maturation. As a result, patients with MDS are at risk for symptomatic anemia, infection, and bleeding, as well as development of acute myeloid leukemia (AML), which is often refractory to treatment. (See "Clinical manifestations and diagnosis of the myelodysplastic syndromes".)
Most patients with MDS die because of the consequences of bone marrow failure rather than development of AML. Thus, use of terms such as "pre-leukemia" or "smoldering leukemia" can be misleading if taken to imply that death or morbidity from MDS results only when AML develops. Indeed, the distinction between MDS and AML is itself arbitrary, as patients with 20 to 30 percent blasts are considered to have MDS by French-American-British (FAB) criteria, but AML by the World Health Organization (WHO) classification.
For many years, transfusion with packed red blood cells and platelets and the use of erythropoiesis stimulating agents were the only therapy available. More recently, chemotherapy agents directed at the underlying disorder have been developed and continue to be studied for patients with MDS (eg, azacitidine, decitabine, and lenalidomide). However, due to the advanced age of most patients, the chronicity of the disease, and its attendant morbidities, supportive care remains a central component of the management of all patients with MDS. Patients should be treated as needed with antibiotics for infection and platelet transfusions for bleeding in the setting of thrombocytopenia. (See "Management of the complications of the myelodysplastic syndromes".)
There is no consensus regarding a standard treatment approach for patients with symptomatic MDS, and patients should be encouraged to enroll on clinical trials whenever available. Our treatment approach incorporates knowledge of the patient’s performance status, the International Prognostic Scoring System (IPSS) (table 1) (calculator 1) and revised IPSS (IPSS-R) (table 2) (calculator 2) MDS risk categories, and other disease characteristics (ie, cytopenias present, serum erythropoietin level) to help guide management decisions.
This topic review will discuss the management of patients with MDS and a high (>4.5 to 6 points) or very high (>6 points) IPSS-R score. The treatment of patients with an intermediate (>3 to 4.5 points), low (>1.5 to 3 points), or very low (≤1.5 points) IPSS-R score, the management of the complications of MDS, details on the use of hematopoietic cell transplantation in MDS, and the prognosis of MDS are discussed separately. (See "Treatment of intermediate, low, or very low risk myelodysplastic syndromes" and "Hematopoietic cell transplantation in myelodysplastic syndromes" and "Prognosis of the myelodysplastic syndromes in adults".)
- http://www.nccn.org/professionals/physician_gls/pdf/mds.pdf (Accessed on September 28, 2013).
- Malcovati L, Hellström-Lindberg E, Bowen D, et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood 2013; 122:2943.
- Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood 2012; 120:2454.
- Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89:2079.
- Appelbaum FR, Anderson J. Allogeneic bone marrow transplantation for myelodysplastic syndrome: outcomes analysis according to IPSS score. Leukemia 1998; 12 Suppl 1:S25.
- Oosterveld M, Wittebol SH, Lemmens WA, et al. The impact of intensive antileukaemic treatment strategies on prognosis of myelodysplastic syndrome patients aged less than 61 years according to International Prognostic Scoring System risk groups. Br J Haematol 2003; 123:81.
- 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 2004; 104:579.
- Koreth J, Pidala J, Perez WS, et al. Role of reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation in older patients with de novo myelodysplastic syndromes: an international collaborative decision analysis. J Clin Oncol 2013; 31:2662.
- Ho AY, Pagliuca A, Kenyon M, et al. Reduced-intensity allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome and acute myeloid leukemia with multilineage dysplasia using fludarabine, busulphan, and alemtuzumab (FBC) conditioning. Blood 2004; 104:1616.
- Spyridonidis A, Bertz H, Ihorst G, et al. Hematopoietic cell transplantation from unrelated donors as an effective therapy for older patients (> or = 60 years) with active myeloid malignancies. Blood 2005; 105:4147.
- Gerds AT, Gooley TA, Estey EH, et al. Pretransplantation therapy with azacitidine vs induction chemotherapy and posttransplantation outcome in patients with MDS. Biol Blood Marrow Transplant 2012; 18:1211.
- Tricot G, Boogaerts MA. The role of aggressive chemotherapy in the treatment of the myelodysplastic syndromes. Br J Haematol 1986; 63:477.
- Wattel E, Solary E, Hecquet B, et al. Quinine improves the results of intensive chemotherapy in myelodysplastic syndromes expressing P glycoprotein: results of a randomized study. Br J Haematol 1998; 102:1015.
- Wu L, Li X, Su J, et al. Effect of low-dose cytarabine, homoharringtonine and granulocyte colony-stimulating factor priming regimen on patients with advanced myelodysplastic syndrome or acute myeloid leukemia transformed from myelodysplastic syndrome. Leuk Lymphoma 2009; 50:1461.
- Estey E, Thall P, Beran M, et al. Effect of diagnosis (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or acute myeloid leukemia [AML]) on outcome of AML-type chemotherapy. Blood 1997; 90:2969.
- Knipp S, Hildebrand B, Kündgen A, et al. Intensive chemotherapy is not recommended for patients aged >60 years who have myelodysplastic syndromes or acute myeloid leukemia with high-risk karyotypes. Cancer 2007; 110:345.
- de Witte T, Suciu S, Verhoef G, et al. Intensive chemotherapy followed by allogeneic or autologous stem cell transplantation for patients with myelodysplastic syndromes (MDSs) and acute myeloid leukemia following MDS. Blood 2001; 98:2326.
- Stone RM. How I treat patients with myelodysplastic syndromes. Blood 2009; 113:6296.
- Kantarjian HM. Treatment of myelodysplastic syndrome: questions raised by the azacitidine experience. J Clin Oncol 2002; 20:2415.
- Sudan N, Rossetti JM, Shadduck RK, et al. Treatment of acute myelogenous leukemia with outpatient azacitidine. Cancer 2006; 107:1839.
- Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009; 10:223.
- Fenaux P, Gattermann N, Seymour JF, et al. Prolonged survival with improved tolerability in higher-risk myelodysplastic syndromes: azacitidine compared with low dose ara-C. Br J Haematol 2010; 149:244.
- Seymour JF, Fenaux P, Silverman LR, et al. Effects of azacitidine compared with conventional care regimens in elderly (≥ 75 years) patients with higher-risk myelodysplastic syndromes. Crit Rev Oncol Hematol 2010; 76:218.
- Itzykson R, Thépot S, Quesnel B, et al. Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine. Blood 2011; 117:403.
- Itzykson R, Thépot S, Quesnel B, et al. Long-term outcome of higher-risk MDS patients treated with azacitidine: an update of the GFM compassionate program cohort. Blood 2012; 119:6172.
- Lübbert M, Suciu S, Baila L, et al. Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol 2011; 29:1987.
- Welch JS, Petti AA, Miller CA, et al. TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. N Engl J Med 2016; 375:2023.
- Sekeres MA, Othus M, List AF, et al. Randomized Phase II Study of Azacitidine Alone or in Combination With Lenalidomide or With Vorinostat in Higher-Risk Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia: North American Intergroup Study SWOG S1117. J Clin Oncol 2017; :JCO2015662510.
- Silverman LR, Verma A, Odchimar-Reissig R, et al. A Phase II Trial Of Epigenetic Modulators Vorinostat In Combination With Azacitidine (azaC) In Patients With The Myelodysplastic Syndrome (MDS): Initial Results Of Study 6898 Of The New York Cancer Consortium. Blood (ASH Annual Meeting Abstracts) 2013; 122:386.
- Sekeres MA, Tiu RV, Komrokji R, et al. Phase 2 study of the lenalidomide and azacitidine combination in patients with higher-risk myelodysplastic syndromes. Blood 2012; 120:4945.
- Swerdlow SH, Campo E, Harris NL, et al. (Eds). World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, IARC Press, Lyon 2008.
- Adès L, Boehrer S, Prebet T, et al. Efficacy and safety of lenalidomide in intermediate-2 or high-risk myelodysplastic syndromes with 5q deletion: results of a phase 2 study. Blood 2009; 113:3947.
- www.aamds.org/aplastic (Accessed on July 12, 2011).
- Walter RB, Gooley TA, Wood BL, et al. Impact of pretransplantation minimal residual disease, as detected by multiparametric flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute myeloid leukemia. J Clin Oncol 2011; 29:1190.
- INDICATIONS FOR TREATMENT
- PRETREATMENT EVALUATION
- INITIAL TREATMENT
- Choice of therapy
- Hematopoietic cell transplantation
- High intensity chemotherapy
- Azacitidine and decitabine
- SPECIAL PATIENT POPULATIONS
- Intermediate risk IPSS-R
- Therapy-related MDS
- Patients with 5q deletion
- Chronic myelomonocytic leukemia
- PATIENT FOLLOW-UP
- TREATMENT OF RECURRENT OR REFRACTORY DISEASE
- CLINICAL TRIALS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS