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The Leukemia/Bone Marrow Transplant Program of BC

Healthcare Professionals
Cancer Management Guidelines

Myelodysplastic Syndrome (MDS)

Updated: January 2013 - currently under review

Diagnosis

Myelodysplastic syndrome (MDS) is a clonal stem cell disorder characterized by low blood counts despite a bone marrow that is usually quite cellular. However, the cells within the bone marrow have an abnormal (“dysplastic”) appearance and frequently are dysfunctional. MDS has a tendency to develop into cancer of the bone marrow (acute leukemia or “AML”) although the speed with which this occurs in MDS is highly variable. Furthermore, patients with MDS may have separate medical problems that have a more significant impact on their quality and duration of life.

Investigations

Patients with low blood counts should have the following performed:

  • Creatinine, electrolytes and liver function testing (including LDH)
  • Serum ferritin
  • B12 levels
  • Reticulocyte count
  • Serum TSH

If no explanation is found for low counts, referral to a hematologist is recommended for:

  • Bone marrow aspirate and biopsy - SENDING A MARROW SAMPLE FOR CYTOGENETIC ANALYSIS IS CRITICAL IN MDS
  • Peripheral blood flow cytometry for paroxysmal nocturnal hemoglobinuria (“PNH”) testing

Patients with either unexplained hematologic cytopenias or documented MDS can be referred to the Marrow Failure Syndromes Clinic at Vancouver General Hospital by sending information by fax to 604-875-4763.

Classification

MDS is currently classified according to the World Health Organization Classification of Hematopoietic and Lymphoid Tumours (2008)1 in the following manner:

Myelodysplastic syndromes

  • Refractory cytopenia with unilineage dysplasia (RCUD)
  • Refractory anemia with ring sideroblasts (RARS)
  • Refractory cytopenia with multilineage dysplasia (RCMD)
  • Refractory anemia with excess blasts (RAEB-1/2)
  • MDS with isolated deletion of 5q
  • MDS, unclassifiable
  • Refractory cytopenia of childhood

Myelodysplastic/Myeloproliferative neoplasms

  • Chronic myelomonocytic leukemia (CMML-1/2)
  • Atypical chronic myeloid leukemia
  • Juvenile myelomonocytic leukemia (JMML)
  • MDS/MPD neoplasm, unclassifiable.

Prognosis

Prognosis in MDS is dependent upon the International Prognostic Scoring System (IPSS; Greenberg, 1997) that was most recently revised in 2012 (IPSS-R).

Revised International Prognostic Scoring System

 

 Score

Variable 

0

0.5

1.0

1.5

2.0

3.0

4.0

Cytogenetic
Group

Very
Good

-

Good

-

Inter-mediate

Poor

Very Poor

Marrow
Blast %

≤ 2

 -

 > 2,
< 5

-

 5-10

 > 10

-

Hemoglobin
g/L

 ≥ 100

 -

 ≥ 80,
< 100 

-

 < 80

-

-

ANC
x 109/L

 ≥ 0.8

 -

 < 0.8

-

-

-

-

Platelets
x 109/L

 ≥ 100

 ≥ 50,
< 100 

 < 50

 

 

 

 

IPSS-R Cytogenetic Risk Groups

  • Very Good: -y, del(11q)
  • Good: Normal, del(5q) ± 1 other, del(12p), del(20q)
  • Intermediate: del(7q) alone, +8, +19, i(17q), any other single or double abnormality
  • Poor: -7, del(7q) with one other abnormality, 3 independent abnormalities
  • Very Poor: ≥ 4 independent abnormalities

Score for each of the factors are added together to arrive at an overall IPSS-R score (see table below), associated with a distinct prognosis. Age, ECOG performance status, serum ferritin or serum Beta-2 microglobulin may also be included to calculate an IPSS-RA*.

 Risk Category 

Score

 Median Survival (yrs) 

 Very Low

 ≤ 1.5

 8.8

 Low

 > 1.5, ≤ 3.0 

 5.3

 Intermediate

 > 3.0, ≤ 4.5

 3.0

 High

 > 4.5, ≤ 6.0 

 1.6

Very High

> 6.0

0.8

Treatment

Treatment recommendations for MDS are largely based upon general health and IPSS-R risk category although all patients require supportive care. Supportive care consists of blood product transfusions and antibiotic/antiviral/antifungal therapy as required. In general, all patients with “high" or "very high" risk MDS according to the IPSS-R scoring system will be evaluated for stem cell transplantation or Azacitidine therapy. Patients with “low” or “very low" risk MDS will only be considered for non-transplantation treatments such as bone marrow “growth factors”, immunosuppressive therapy or immunomodulatory agents (IMiDs). Depending upon the IPSS-RA* and other unique features of a patient's MDS, an intermediate-risk patient may be considered for Azacitidine or stem cell transplantation as well. At certain times, an MDS patient may be eligible for participation in a clinical trial, usually designed to evaluate a potential (but unproven) drug or combination of drugs for treating MDS. This general approach is outlined in the Treatment Algorithm.

Transfusion support

Red cell transfusions can provide symptomatic relief (of fatigue and dyspnea) for MDS patients but the transfusion threshold varies from patient to patient, depending upon age, activity level and other medical problems (especially heart and lung disease). In general, red cells should be considered for a hemoglobin <80 g/L but in the presence of heart disease, transfusions may be needed if the hemoglobin is <100 g/L. Patients that have had ≥25 units of red cells and a serum ferritin >1000-1500 will be considered for iron chelation therapy provided they have very low, low or intermediate risk MDS. Platelet transfusions are often given when the platelet count is <10 x 109/L and may be required more than once weekly. However, patients with clinical bleeding issues may have to have a higher transfusion threshold (i.e., <20-30 x 109/L) while those without bleeding may not need (or wish) to have preemptive platelet transfusions.

Allogeneic stem cell transplantation

Stem cell transplantation (SCT) is the only proven curative treatment for MDS but is generally reserved for high or very high risk patients because of the significant risk involved. Furthermore, patients must have a suitable related or unrelated or cord blood donor and be free of other medical illnesses to safely undergo this procedure. Unfortunately about 1/3 of MDS patients die of complications of SCT during the first year and another 1/3 of patients experience a relapse of their MDS. Bearing all of this in mind, 30-35% of patients that have undergone allogeneic SCT have been long-term survivors.

Azacitidine

Azacitidine is a low-dose chemotherapy agent that is given primarily in high and very high risk MDS by subcutaneous injection for 7 days every 4 weeks (See Protocols/PPOs). It is a well-tolerated drug that has been shown in a randomized study, to improve quality of life and prolong survival by an average of 9-10 months when compared to supportive care alone. It is not considered to be a curative drug. Azacitidine may cause nausea, constipation or diarrhea, inflammation at the injection site and, initially, worsening of blood counts. It is helpful in about 50% of patients with MDS but it may take 4-6 months before a benefit is seen.

Growth factors

In MDS patients with a relatively isolated anemia, a red cell stimulant, either Erythropoietin (Eprex) or Darbepoietin (Aranesp), given by injection once weekly, will alleviate the anemia for a period of time, in 25-50% of cases.6 In patients with a relatively isolated low platelet count, a similar transient response rate can be seen with weekly Romiplostim (Nplate) injections.7  In MDS patients with serious infections associated with a low white cell count, Granulocyte-colony stimulating factor (G-CSF; Neupogen; Filgrastim) can be given to increase white cell (neutrophil) production although its effects are short-lived. All growth factor therapy is expensive, access to these agents may be limited and none have been convincingly shown to prolong survival in MDS patients.

Immunosuppression

Some MDS patients have a more “underactive” (hypocellular) bone marrow that resembles a bone marrow failure disorder called “aplastic anemia”. These patients appear to have bone marrow damage as a result of an inappropriately overactive immune system. Treatment with drugs to suppress the immune system (immunosuppression), such as Cyclosporine and Antithymocyte globulin (ATG; ATGAM), can improve blood counts in about 30% of patients although response is typically slow. Immunosuppressive treatment is started in hospital and includes a combination of Cyclosporine and intravenous anti-thymocyte globulin (ATGAM) (See Protocols/PPOs). Because allergic reactions can occur with ATG and can occasionally be severe, MDS patients treated with this agent are kept in hospital for about one week.

Immunomodulatory drugs (IMiDs)

Thalidomide is an oral drug that, in the past, has been associated with major birth defects when given to pregnant women. However, it has been used in a number of other conditions and has been shown to improve hemoglobin levels in about 30% of lower risk MDS patients. Thalidomide can cause sedation, constipation and nerve damage (neuropathy) and these side effects led to the development of Lenalidomide (Revlimid), a related drug associated with less sedation and neuropathy. Revlimid is more effective than Thalidomide, especially in MDS patients with deletion of chromosome 5q [del(5q)], and it has been licensed for use in del(5q) patients since 2008 (See Protocols/PPOs). Revlimid is rarely used outside of this unique patient subgroup and drug access, outside of a clinical trial, can be problematic for non-del(5q) MDS patients.

Algorithms

Click image to enlarge.

MDS Treatment Algorithm

Protocols

BCCA Chemotherapy Protocols and PPOs

Publications

  1. WHO Classification of tumours of haematopoietic and lymphoid tissues 4th edition. Eds. Swerdlow SH et al. International agency for research on cancer. Lyon, France, 2008.
  1. Peter Greenberg, Christopher Cox, Michelle M. LeBeau, Pierre Fenaux, Pierre Morel, Guillermo Sanz, Miguel Sanz, Teresa Vallespi, Terry Hamblin, David Oscier, Kazuma Ohyashiki, Keisuke Toyama, Carlo Aul, Ghulam Mufti, and John Bennett. International Scoring System for Evaluating Prognosis in Myelodysplastic Syndromes. Blood 89:2079-2088, 1997.
  2. Thomas J. Nevill, John D. Shepherd, Heather J. Sutherland, Yasser R. Abou Mourad, Julye C. Lavoie, Michael J. Barnett, Stephen H. Nantel, Cynthia L. Toze, Donna E. Hogge, Donna L. Forrest, Kevin W. Song, Maryse M. Power, Janet Y. Nitta, Yunfeng Dai, Clayton A. Smith. IPSS Poor-Risk Karyotype as a Predictor of Outcome for Patients with Myelodysplastic Syndrome following Myeloablative Stem Cell Transplantation. Biol Blood Marrow Transplant 15:205-213, 2009.
  3. Lewis R. Silverman, Erin P. Demakos, Bercedis L. Peterson, Alice B. Kornblith, Jimmie C. Holland, Rosalie Odchimar-Reissig, Richard M. Stone, Douglas Nelson, Bayard L. Powell, Carlos M. DeCastro, John Ellerton, Richard A. Larson, Charles A. Schiffer, and James F. Holland. Randomi zed 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.
  4. Pierre Fenaux, Ghulam J Mufti, Eva Hellstrom-Lindberg, Valeria Santini, Carlo Finelli, Aristoteles Giagounidis, Robert Schoch, Norbert Gattermann, Guillermo Sanz, Alan List, Steven D Gore, John F Seymour, John M Bennett, John Byrd, Jay Backstrom, Linda Zimmerman, David McKenzie, C L Beach, Lewis R Silverman, for the International Vidaza High-Risk MDS Survival Study Group. 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 10:223-232, 2009.
  5. Eva Hellström-Lindberg, Nina Gulbrandsen, Greger Lindberg, Tomas Ahlgren, Inger Marie S. Dahl, Ingunn Dybedal, Gunnar Grimfors, Eva Hesse-Sundin, Martin Hjorth, Lena Kanter-Lewensohn, Olle Linder,9 Michaela Luthman, Eva Löfvenberg, Gunnar Öberg, Anja Porwit-MacDonald, Anders Rådlund, Jan Samuelsson, Jon Magnus Tangen, Ingemar Winquist and Finn Wisloff for the Scandinavian MDS Group. 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.
  6. Hagop Kantarjian, Pierre Fenaux, Mikkael A. Sekeres, Pamela S. Becker, Adam Boruchov, David Bowen, Eva Hellstrom-Lindberg, Richard A. Larson, Roger M. Lyons, Petra Muus, Jamile Shammo, Robert Siegel, Kuolung Hu, Janet Franklin, and Dietmar P. Berger. Safety and Efficacy of Romiplostim in Patients With Lower-Risk Myelodysplastic Syndrome and Thrombocytopenia. J Clin Oncol 28:437-444, 2010.
  7. Yogen Saunthararajah, Ryotaro Nakamura, Robert Wesley, Qiong J. Wang, and A. John Barrett. A simple method to predict response to immunosuppressive therapy in patients with myelodysplastic syndrome. Blood 102:3025-3027, 2003.
  8. Azra Raza, Peter Meyer, Diya Dutt, Francesca Zorat, Laurie Lisak, Fabiana Nascimben, Morne du Randt, Christopher Kaspar, Cathryn Goldberg, Jerome Loew, Saleem Dar, Sefer Gezer, Parameswaran Venugopal, and Jerome Zeldis. Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes. Blood 98:958-965, 2001.
  9. Alan List, Sandy Kurtin, Denise J. Roe, Andrew Buresh, Daruka Mahadevan, Deborah Fuchs, Lisa Rimsza, Ruth Heaton, Robert Knight, and Jerome B. Zeldis. Efficacy of Lenalidomide in Myelodysplastic Syndromes. N Engl J Med 352: 549-57, 2005.
  10. Alan List, Gordon Dewald, John Bennett, Aristotle Giagounidis, Azra Raza, Eric Feldman, Bayard Powell, Peter Greenberg, Deborah Thomas, Richard Stone, Craig Reeder, Kenton Wride, John Patin, Michele Schmidt, Jerome Zeldis, and Robert Knight, for the Myelodysplastic Syndrome-003 Study Investigators. Lenalidomide in the Myelodysplastic Syndrome with Chromosome 5q Deletion. N Engl J Med 355: 1456-1465, 2006.
  11. Peter Greenberg, Heinz Tuechler, Julie Schanz, Guillermo Sanz, Guillermo Garcia-Manero, Francesco Solé, John Bennett, David Bowen, Pierre Fenaux, François Dreyfus, Hagop Kantarjian, Andrea Kuendgen, Alessandro Levis, Luca Malcovati, Mario Cazzola, Jaroslav Cermak, Christa Fonatsch, Michelle Le Beau, Marilyn Slovak, Otto Krieger, Michael Luebbert, Jaroslav Maciejewski, Silvia Magalhaes, Yasushi Miyazaki, Michael Pfeilstöcker, Mikael Sekeres, Wolfgang Sperr, Reinhard Stauder, Sudhir Tauro, Peter Valent, Teresa Vallespi, Arjan van de Loosdrecht, Ulrich Germing, Detlef Haase. Revised International Prognostic Scoring System for Myelodysplastic Syndromes. Blood 120: 2454-2465, 2012.

 

The information contained in these guidelines is a statement of consensus of Leukemia/BMT Program of BC professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult these documents is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patientís care or treatment. Use of these guidelines and documents is at your own risk and is subject to the Leukemia/BMT Program of BCís terms of use available at Terms of Use.

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